Transdermal therapeutic system containing asenapine

ABSTRACT

The present invention relates to transdermal therapeutic systems (TTS) for the transdermal administration of asenapine comprising a self-adhesive layer structure containing a therapeutically effective amount of asenapine, such asenapine TTS for use in a method of treatment, processes of manufacture of such TTS as well as asenapine and transdermal therapeutic systems containing asenapine for use in a method of treatment and to a method of treating a human patient by transdermal administration of asenapine.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a transdermal therapeutic system (TTS)for the transdermal administration of asenapine to the systemiccirculation, and processes of manufacture, method of treatments and usesthereof.

BACKGROUND OF THE INVENTION

The active agent asenapine(3aRS,12bRS)-rel-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole)is an atypical antipsychotic belonging to the dibenzo-oxepino pyrrolefamily, the tetracyclic structure of which is unrelated to those ofother antipsychotics such as Olanzapine, Quetiapine or Clozapine(tricyclic structure), Risperidone, Ziprasidone or Aripiprazole(bicyclic structure). Asenapine is an antagonist at the dopamine D2 andserotonin 5-HT2A receptors with high affinity to the latter and has beendeveloped by Schering-Plough/Organon for the treatment of schizophreniaand acute mania associated with bipolar disorder.

Currently, asenapine is commercially available in the form of sublingualtablets, which is administered in dosage strengths of 2.5 mg, 5 mg or 10mg twice daily (BID) under the brand names Sycrest (Swissmedic) andSaphris (Schering-Plough).

The sublingual administration route avoids the first-pass metabolism ofan oral administration in order to increase bioavailability, which is at35% when taken sublingually and <2% if ingested. However, sublingualadministration is associated with bitter or unpleasant taste as well astongue/oral mucosal numbness induced by a local anesthetic effect,nausea and headaches. Further, eating, drinking and smoking are notallowed immediately after sublingual dosing for 10 min. Theseinconveniences may lead to reduced patient compliance and improperadministration such as dose reduction, dose skipping, irregular drugintake or a complete abstinence from the intended asenapine intake.Sublingual administration is also difficult to monitor ininstitutionalized psychiatric patients and may not be suitable forchildren, elderly and other patients with difficulty in swallowing, orfor those not capable of taking medication on their own.

Asenapine shows side effects which are not unusual for a neurolepticdrug. Somnolence and anxiety are very common (observed in ≥10% of thepatients). Other common (≥1% to <10% of the patients) adverse effectsinclude weight gain and increased appetite, nervous system disorderssuch as dystonia, akathisia, dyskinesia, parkinsonism, sedation,dizziness, dysgeusia; gastrointestinal disorders such as oralhypoesthesia, nausea, increased salivation; increases in alanineaminotransferase (ALT), muscle rigidity, and fatigue (tiredness).

Asenapine is metabolized hepatically, mainly via CYP1A2 and UGT1A4(glucuronidation). The clinical relevance of the main human metabolitesN-desmethyl-asenapine and asenapine N+ glucuronide remain controversial.It at least appears that the metabolites would not substantiallyparticipate in the therapeutic effect. Thus, a decrease in the amount ofthese metabolites appears generally desirable.

Following sublingual administration, asenapine is rapidly absorbed withpeak blood plasma concentrations occurring within 0.5 to 1.5 hours and(in therapeutic doses) exhibits 2-compartment pharmacokinetics with arapid initial distribution phase with a half-life of several hours,followed by a longer terminal disposition half-life of around 1 day orlonger. The blood plasma concentration thus exhibits a certain degree offluctuation with peaks about 1 hour post-dose, followed by aconcentration decrease resulting in a low point just before the nextdose, even in steady state. The relatively rapid concentration decreasealso inevitably leads to multiple daily doses (currently twice daily),which are associated with poor patient compliance, in particular inchronic conditions.

Such fluctuation could be avoided, or at least reduced by transdermaladministration of asenapine, which prevents plasma concentrationdecrease between two doses to some extent by providing an extendedrelease of the active. Transdermal delivery of asenapine has beeninvestigated, but it appears that passive transdermal delivery ofasenapine, and in particular a constant release over an extended periodof time, is challenging. Passive transport of active agents from atransdermal therapeutic system (TTS) through the skin makes use of thedriving force based on the concentration gradient between theconcentration of active agent in the transdermal system and on the outersurface of the skin and the concentration in the blood stream. Suchpassive transport is advantageous in view of complexity of the TTS andthe convenience of administration compared to TTS making use of activetransportation such as iontophoresis or microporation. Up to date, nocommercial asenapine TTS is available.

The inventors have previously developed a transdermal therapeutic systemfor the transdermal administration of asenapine overcoming theabove-mentioned disadvantages of current asenapine administration. Inparticular, a TTS was developed which is able to provide a permeationrate sufficient for achieving a therapeutically effective dose, which isadequate for a continuous administration of asenapine for administrationperiods of up to 7 days, e.g. 3.5 days, and which is also easy andcost-efficient to manufacture.

However, in terms of stability of the manufactured TTS, in particularwith respect to the content of active and active degradation, initiallyas well as upon storage, the previously developed formulation still hasroom for improvement. There is thus a need for improved asenapine TTSformulations that provide better stability without impairing theadvantageous skin permeation rates.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a TTS overcoming theabove-mentioned disadvantages of current asenapine administration.

Thus, it is an object of the present invention to provide a TTS, and inparticular a matrix-type TTS, for the transdermal administration ofasenapine, with improved stability, and at the same time providing apermeation rate which is sufficient for achieving a therapeuticallyeffective dose, in particular in a continuous administration, providingtherapeutically effective amounts of asenapine for up to 7 days, duringan administration period to the skin of the patient of up to 7 days(e.g. 3.5 days).

It is also an object of the present invention to provide a TTS, and inparticular a matrix-type TTS, for the transdermal administration ofasenapine, with improved stability, wherein the fluctuation in asenapineblood plasma concentration is reduced when compared to sublingualadministration, in particular in steady state.

It is another object of the present invention to provide a TTS, and inparticular a matrix-type TTS, for the transdermal administration ofasenapine, with improved stability, and which complies with the needs ofa convenient application in view of size and thickness and/or which iseasy and cost-efficient to manufacture.

These objects and others are accomplished by the present invention,which according to one aspect relates to a transdermal therapeuticsystem for the transdermal administration of asenapine comprising aself-adhesive layer structure containing a therapeutically effectiveamount of asenapine, said self-adhesive layer structure comprising:

A) a backing layer;

B) an asenapine-containing matrix layer consisting of a matrix layercomposition comprising:

-   -   1. asenapine; and    -   2. a polymer selected from acrylic polymers    -   3. an additional polymer; and    -   4. α-tocopherol in an amount of from 0.01 to 2% of the matrix        layer composition and ascorbyl palmitate in an amount of at        least 0.01% of the matrix layer composition as stabilizers

According to certain embodiments of the invention, the transdermaltherapeutic system according to the invention is for use in a method oftreatment, preferably for use in a method of treating psychosis and morepreferably for use in a method of treating one or more conditionsselected from schizophrenia, bipolar disorder, posttraumatic stressdisorder, major depressive disorder, dementia related psychosis,agitation and manic disorder, in particular during administration for anextended period of time.

Thus, according to certain embodiments of the invention, the transdermaltherapeutic system according to the invention is for use in a method oftreating schizophrenia and/or bipolar disorder during an administrationperiod of about 24 hours to about 168 hours, or 1 to 7 days, and inparticular for use in a method of treating schizophrenia and/or bipolardisorder during an administration period of about 24 hours, or 1 day, ofabout 48 hours, or 2 days, or of about 84 hours, or 3.5 days.

According to other embodiments, the present invention relates to amethod of treatment, and in particular a method of treating psychosisand more preferably a method of treating one or more conditions selectedfrom schizophrenia, bipolar disorder, posttraumatic stress disorder,major depressive disorder, dementia related psychosis, agitation andmanic disorder, including applying a transdermal therapeutic systemaccording to the invention to the skin of a patient for an extendedperiod of time.

Thus, according to certain other embodiments, the invention relates to amethod of treating schizophrenia and/or bipolar disorder includingapplying a transdermal therapeutic system according to the invention forabout 24 hours to about 168 hours or for 1 to 7 days, or for about 24hours, 48 hours or 84 hours, or for 1 day, 2 days or 3.5 days to theskin of a patient.

Such modes of administration require a once a day, once each two days,twice a week or a once a week exchange of the TTS in an around-the-clocktreatment.

According to yet another specific aspect, the invention relates to aprocess of manufacture of a matrix layer for use in a transdermaltherapeutic system comprising the steps of:

1) combining at least the components asenapine, acrylic polymer,additional polymer, α-tocopherol and ascorbyl palmitate, in a solvent toobtain a coating composition;

2) coating the coating composition onto a backing layer or a releaseliner or any intermediate liner; and 3) drying the coated coatingcomposition to form the matrix layer.

According to certain embodiments the invention also relates to atransdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure comprising:

A) a backing layer;

B) an asenapine-containing matrix layer consisting of a matrix layercomposition comprising:

-   -   1. asenapine included in the form of the free base;    -   2. a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate,        2-hydroxyethyl-acrylate and glycidyl-methacrylate or a copolymer        based on vinyl acetate,    -   2-ethylhexyl-acrylate and 2-hydroxyethyl-acrylate;    -   3. medium chain triglycerides in an amount of from 5 to 12% of        the matrix layer composition;    -   4. soluble polyvinylpyrrolidone in an amount of from 5 to 15% of        the matrix layer composition; and    -   5. α-tocopherol in an amount of from 0.025 to 0.1% of the matrix        layer composition, ascorbyl palmitate in an amount of from 0.15        to 0.5% of the matrix layer composition, and sodium        metabisulfite in an amount of from 0.05 to 0.15% of the matrix        layer composition, as stabilizers;

Within the meaning of this invention, the term “transdermal therapeuticsystem” (TTS) refers to a system by which the active agent (asenapine)is administered to the systemic circulation via transdermal delivery andrefers to the entire individual dosing unit that is applied to the skinof a patient, and which comprises a therapeutically effective amount ofasenapine in a self-adhesive layer structure and optionally anadditional adhesive overlay on top of the asenapine-containingself-adhesive layer structure. The self-adhesive layer structure may belocated on a release liner (a detachable protective layer), thus, theTTS may further comprise a release liner. Within the meaning of thisinvention, the term “TTS” in particular refers to a system providingpassive transdermal delivery excluding active transport as in methodsincluding iontophoresis or microporation.

Within the meaning of this invention, the term “asenapine-containingself-adhesive layer structure” or “self-adhesive layer structurecontaining a therapeutically effective amount of asenapine” refers tothe active agent-containing structure providing the area of release forasenapine during administration. The adhesive overlay adds to theoverall size of the TTS but does not add to the area of release. Theasenapine-containing self-adhesive layer structure comprises a backinglayer and at least one asenapine-containing layer.

Within the meaning of this invention, the term “therapeuticallyeffective amount” refers to a quantity of active agent in the TTSsufficient to provide, if administered by the TTS to a patient,asenapine blood levels of a similar range (e.g. of about 10% to about1000% as measured as an AUC) when compared to blood levels obtained insteady state administration of twice daily 5 mg sublingual asenapineover a predefined extended period of time (e.g. 1, 3.5 and 7 days). ATTS usually contains more active in the system than is in fact providedto the skin and the systemic circulation. This excess amount of activeagent is usually necessary to provide enough driving force for thepassive transportation from the TTS to the systemic circulation.

Within the meaning of this invention, the terms “active”, “activeagent”, and the like, as well as the term “asenapine” refer to asenapinein any pharmaceutically acceptable chemical and morphological form andphysical state. These forms include without limitation asenapine in itsfree base form, protonated or partially protonated asenapine, asenapinesalts and in particular acid addition salts formed by addition of aninorganic or organic acid such as asenapine hydrochloride or asenapinemaleate, hydrates, complexes and so on, as well as asenapine in the formof particles which may be micronized, crystalline and/or amorphous, andany mixtures of the aforementioned forms. The asenapine, where containedin a medium such as a solvent, may be dissolved or dispersed or in partdissolved and in part dispersed.

When asenapine is mentioned to be used in a particular form in themanufacture of the TTS, this does not exclude interactions between thisform of asenapine and other ingredients of the asenapine-containingself-adhesive layer structure, e.g. salt formation or complexation, inthe final TTS. This means that, even if asenapine is included in itsfree base form, it may be present in the final TTS in protonated orpartially protonated form or in the form of an acid addition salt, or,if it is included in the form of a salt, parts of it may be present asfree base in the final TTS. Unless otherwise indicated, in particularthe amount of asenapine in the self-adhesive layer structure relates tothe amount of asenapine included in the TTS during manufacture of theTTS and is calculated based on asenapine in the form of the free base.E.g., when a) 0.1 mmol (equal to 28.6 mg) asenapine base or b) 0.1 mmol(equal to 40.2 mg) asenapine maleate is included in the TTS duringmanufacture, the amount of asenapine in the self-adhesive layerstructure is, within the meaning of the invention, in both cases 0.1mmol or 28.6 mg.

The asenapine starting material included in the TTS during manufactureof the TTS may be in the form of particles. Asenapine may e.g. bepresent in the self-adhesive layer structure in the form of particlesand/or dissolved.

Within the meaning of this invention, the term “particles” refers to asolid, particulate material comprising individual particles, thedimensions of which are negligible compared to the material. Inparticular, the particles are solid, including plastic/deformablesolids, including amorphous and crystalline materials.

Within the meaning of this invention, the term “dispersing” refers to astep or a combination of steps wherein a starting material (e.g.asenapine) is not totally dissolved. Dispersing in the sense of theinvention comprises the dissolution of a part of the starting material(e.g. asenapine particles), depending on the solubility of the startingmaterial (e.g. the solubility of asenapine in the coating composition).

There are two main types of TTS using passive active agent delivery,i.e. matrix-type TTS and reservoir-type TTS. In matrix-type TTS theactive agent is included in a matrix, while in a reservoir-type TTS theactive agent is included in a liquid or semi-liquid reservoir. Therelease of the active agent in a matrix-type TTS is mainly controlled bythe matrix including the active agent itself In contrast thereto, areservoir-type TTS needs a rate-controlling membrane controlling therelease of the active agent. Matrix-type TTS are advantageous in that,compared to reservoir type TTS, usually no rate determining membranesare necessary and no dose dumping can occur due to membrane rupture. Insummary, matrix-type transdermal therapeutic systems (TTS) are lesscomplex in manufacture and easy and convenient to use by patients.

Within the meaning of this invention, “matrix-type TTS” refers to asystem or structure wherein the active is homogeneously dissolved and/ordispersed within a polymeric carrier, i.e. the matrix, which forms withthe active agent and optionally remaining ingredients a matrix layer. Insuch a system, the matrix layer controls the release of the active agentfrom the TTS. A matrix-type TTS may also include a rate-controllingmembrane.

TTS with a rate-controlling membrane and a liquid or semi-liquid activeagent containing reservoir, wherein the release of the active agent fromthe TTS is controlled by the rate-controlling membrane, are referred toby the term “reservoir-type TTS”. Reservoir-type TTS are not to beunderstood as being of matrix-type within the meaning of the invention.In particular, within the meaning of this invention,microreservoir-systems (biphasic systems having an inneractive-containing phase in an outer matrix-phase), considered in the artto be a mixture between a matrix-type TTS and a reservoir-type TTS, areconsidered to be of matrix-type within the meaning of the invention.Matrix-type TTS may in particular be in the form of a“drug-in-adhesive”-type TTS referring to a system wherein the active ishomogeneously dissolved and/or dispersed within a pressure-sensitiveadhesive matrix.

Within the meaning of this invention, the term “matrix layer” refers toany layer containing the active homogeneously dissolved and/or dispersedwithin a polymeric carrier. Typically, a matrix layer is present in amatrix-type TTS as the active agent-containing layer. A reservoir-typeTTS may comprise, in addition to a reservoir layer and arate-controlling membrane, an additional adhesive layer which serves asa skin contact layer. In such a reservoir-type TTS, the additionaladhesive layer often is manufactured as an active agent-free layer.However, due to the concentration gradient, the active agent willmigrate from the reservoir to the additional adhesive layer over time,until an equilibrium is reached. Therefore, in such a reservoir-typeTTS, after some time of equilibration, the additional adhesive layercontains the active agent and is to be regarded as a matrix layer in thesense of the present invention.

The matrix layer is the final, solidified layer e.g. obtained aftercoating and drying the solvent-containing coating composition. Thematrix layer may also be manufactured by laminating two or more suchsolidified layers (e.g. dried layers) of the same composition to providethe desired area weight. The matrix layer may be self-adhesive (in theform of a pressure sensitive adhesive matrix) or the TTS may comprise anadditional skin contact layer of a pressure sensitive adhesive forproviding sufficient tack. In particular, the matrix layer is a pressuresensitive adhesive matrix.

Within the meaning of this invention, the term “pressure-sensitiveadhesive” refers to a material that in particular adheres with fingerpressure, is permanently tacky, exerts a strong holding force and shouldbe removable from smooth surfaces without leaving a residue. A pressuresensitive adhesive layer, when in contact with the skin, is“self-adhesive”, i.e. provides adhesion to the skin so that typically nofurther aid for fixation on the skin is needed. A “self-adhesive” layerstructure includes a pressure sensitive adhesive layer for skin contactwhich may be provided in the form of a pressure sensitive adhesivematrix or in the form of an additional layer, i.e. a pressure sensitiveadhesive skin contact layer. An adhesive overlay may still be employedto advance adhesion.

Within the meaning of this invention, the term “skin contact layer”refers to a layer included in the TTS to be in direct contact with theskin of the patient during administration. When the TTS comprises a skincontact layer, the other layers do not contact the skin and do notnecessarily have self-adhesive properties. As outlined above, the skincontact layer may over time absorb parts of the active agent and thenmay be regarded as a matrix layer. The area of release is provided bythe area of the matrix layer. A skin contact layer may be used toenhance adherence. The sizes of an additional skin contact layer and thematrix layer are usually coextensive and correspond to the area ofrelease.

Within the meaning of this invention, the term “area weight” refers tothe dry weight of a specific layer, e.g. of the matrix layer, providedin g/m². The area weight values are subject to a tolerance of ±10%,preferably ±7.5%, due to manufacturing variability.

If not indicated otherwise “%” refers to weight-%.

Within the meaning of this invention, the term “polymer” refers to anysubstance consisting of so-called repeating units obtained bypolymerizing one or more monomers, and includes homopolymers whichconsist of one type of monomer and copolymers which consist of two ormore types of monomers. Polymers may be of any architecture such aslinear polymers, star polymer, comb polymers, brush polymers, of anymonomer arrangements in case of copolymers, e.g. alternating,statistical, block copolymers, or graft polymers. The minimum molecularweight varies depending on the polymer type and is known to the skilledperson. Polymers may e.g. have a molecular weight above 2,000,preferably above 5,000 and more preferably above 10,000 Dalton.Correspondingly, compounds with a molecular weight below 2,000,preferably below 5,000 or more preferably below 10,000 Dalton areusually referred to as oligomers.

Within the meaning of this invention, the term “functional groups”refers to hydroxy- and carboxylic acid groups.

Within the meaning of this invention, the term “cross-linking agent”refers to a substance which is able to cross-link functional groupscontained within the polymer.

Within the meaning of this invention, the term “adhesive overlay” refersto a self-adhesive layer structure that is free of active agent andlarger in area than the active agent-containing structure and providesadditional area adhering to the skin, but no area of release of theactive agent. It enhances thereby the overall adhesive properties of theTTS. The adhesive overlay comprises a backing layer and an adhesivelayer.

Within the meaning of this invention, the term “backing layer” refers toa layer, which supports e.g. the asenapine-containing layer or forms thebacking of the adhesive overlay. At least one backing layer in the TTSand usually the backing layer of the asenapine-containing layer isocclusive, i.e. substantially impermeable to the active agent containedin the layer during the period of storage and administration and thusprevents active loss or cross-contamination in accordance withregulatory requirements.

The TTS according to the present invention can be characterized bycertain parameters as measured in an in vitro skin permeation test.

The in vitro permeation test is performed in a Franz diffusion cell,with human or animal skin and preferably with dermatomed split-thicknesshuman skin with a thickness of 800 gm and an intact epidermis, and withphosphate buffer pH 5.5 or 7.4 as receptor medium (32° C. with 0.1%saline azide) with or without addition of a maximum of 40 vol-% organicsolvent e.g. ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG400 so that a receptor medium may e.g. contain 60 vol-% phosphate bufferpH 5.5, 30 vol-% dipropylene glycol and 10 vol-% acetonitrile.

Where not otherwise indicated, the in vitro permeation test is performedwith dermatomed split-thickness human skin with a thickness of 800 gmand an intact epidermis, and with phosphate buffer pH 5.5 as receptormedium (32° C. with 0.1% saline azide). The amount of active permeatedinto the receptor medium is determined in regular intervals using avalidated HPLC method with a UV photometric detector by taking a samplevolume. The receptor medium is completely or in part replaced by freshmedium when taking the sample volume, and the measured amount of activepermeated relates to the amount permeated between the two last samplingpoints and not the total amount permeated so far.

Thus, within the meaning of this invention, the parameter “permeatedamount” is provided in μg/cm² and relates to the amount of activepermeated in a sample interval at certain elapsed time. E.g., in an invitro permeation test as described above, wherein the amount of activepermeated into the receptor medium has been e.g. measured at hours 0, 2,4, 8, 12 and 24, the “permeated amount” of active can be given e.g. forthe sample interval from hour 8 to hour 12 and corresponds to themeasurement at hour 12.

The permeated amount can also be given as a “cumulative permeatedamount”, corresponding to the cumulated amount of active permeated at acertain point in time. E.g., in an in vitro permeation test as describedabove, wherein the amount of active permeated into the receptor mediumhas been e.g. measured at hours 0, 2, 4, 8, 12 and 24, the “cumulativepermeated amount” of active at hour 12 corresponds to the sum of thepermeated amounts from hour 0 to hour 2, hour 2 to hour 4, hour 4 tohour 8 and hour 8 to hour 12.

Within the meaning of this invention, the parameter “skin permeationrate” for a certain sample interval at certain elapsed time is providedin μg/(cm² h) and is calculated from the permeated amount in said sampleinterval as measured by in vitro permeation test as described above inμg/cm², divided by the hours of said sample interval. E.g. the skinpermeation rate in an in vitro permeation test as described above,wherein the amount of active permeated into the receptor medium has beene.g. measured at hours 0, 2, 4, 8, 12 and 24, the “skin permeation rate”at hour 12 is calculated as the permeated amount in the sample intervalfrom hour 8 to hour 12 divided by 4 hours.

A “cumulative skin permeation rate” can be calculated from therespective cumulative permeated amount by dividing the cumulativepermeated amount by the elapsed time. E.g. in an in vitro permeationtest as described above, wherein the amount of active permeated into thereceptor medium has been e.g. measured at hours 0, 2, 4, 8, 12 and 24,the “cumulative skin permeation rate” at hour 12 is calculated as thecumulative permeated amount for hour 12 (see above) divided by 12 hours.

Within the meaning of this invention, the above parameters permeatedamount and skin permeation rate (as well as cumulative permeated amountand cumulative skin permeation rate) refer to mean values calculatedfrom 3 in vitro permeation test experiments.

The TTS according to the present invention can also be characterized bycertain parameters as measured in an in vivo clinical study.

Within the meaning of this invention, the parameter “mean release rate”refers to the mean release rate in μg/h, in mg/h, in μg/24 h, in mg/24h, in μg/day or in mg/day over the period of administration (e.g. 1 to 7day(s)) by which the active agent is released through the human skininto the systemic circulation and is based on the AUC obtained over saidperiod of administration in a clinical study. The mean release rate is aparameter used to identify the dose or the strength of a TTS. Since, incontrast to e.g. intravenous or oral administration and (as alsodescribed above) a TTS usually contains more active in the system thanis in fact provided to the skin and the systemic circulation, the amountof active contained in the TTS is not meaningful as a parameter for thedose. This is why for a TTS the dose or strength is usuallycharacterized by the mean release rate, which describes more accuratelythe amount of active delivered to the subject over time.

Within the meaning of this invention, the term “extended period of time”relates to a period of at least or about 24 hours, at least or about 48hours, at least or about 84 hours, at least or about 168 hours, at leastor about 1 day, at least or about 3.5 days, or at least or about 7 days,or to a period of about 24 hours to about 168 hours or 1 to 7 day(s), orabout 24 hours to about 84 hours or 1 to 3.5 day(s).

For a continuous drug treatment, the frequency of drug administration ispreferably kept sufficiently high so as to maintain a therapeuticallyeffective blood plasma concentration. In other words, the intervalbetween two dosage form administrations, also called dosing interval,needs to be adapted accordingly. Within the meaning of the presentinvention, the term “dosing interval” refers to the period of timebetween two consecutive TTS administrations, i.e. the interval betweentwo consecutive points in time a TTS is applied to the skin of thepatient. Once applied, the TTS is usually maintained on the skin of thepatient for the entire dosing interval and only removed at the end ofthe dosing interval, at which time a new TTS is applied to the skin.E.g., if the dosing interval is 168 hours or 7 days, the TTS is appliedto and maintained on the skin of the patient for 168 hours or 7 days.After 168 hours or 7 days, the TTS is removed from the skin and a newTTS is applied. Thus, a dosing interval of 168 hours or 7 days allows aonce-a-week TTS exchange mode in an around-the-clock treatment.

Within the meaning of this invention, the term “room temperature” refersto the unmodified temperature found indoors in the laboratory where theexperiments are conducted and usually lies within 15 to 35° C.,preferably about 18 to 25° C.

Within the meaning of this invention, the term “patient” refers to asubject who has presented a clinical manifestation of a particularsymptom or symptoms suggesting the need for treatment, who is treatedpreventatively or prophylactically for a condition, or who has beendiagnosted with a condition to be treated.

Within the meaning of this invention the term “pharmacokineticparameters” refers to parameters describing the blood plasma curve, e.g.C_(max), C_(t) and AUC_(t1-t2) obtained in a clinical study, e.g. bysingle-dose, multi-dose or steady state administration of the activeagent TTS, e.g. the asenapine TTS to healthy human subjects. Thepharmacokinetic parameters of the individual subjects are summarizedusing arithmetic and geometric means, e.g. a mean C_(max), a meanAUC_(t) and a mean AUC_(INF), and additional statistics such as therespective standard deviations and standard errors, the minimum value,the maximum value, and the middle value when the list of values isranked (Median). In the context of the present invention,pharmacokinetic parameters, e.g. the C_(max), C_(t) and AUC_(t1-t2)refer to arithmetic or geometric mean values and preferably refer togeometric mean values. It cannot be precluded that the absolute meanvalues obtained for a certain TTS in a clinical study vary to a certainextent from study to study. To allow a comparison of absolute meanvalues between studies, a reference formulation, e.g. in the future anyproduct based on the invention, may be used as internal standard. Acomparison of the AUC per area of release of the respective referenceproduct in the earlier and later study can be used to obtain acorrection factor to take into account differences from study to study.

Clinical studies according to the present invention refer to studiesperformed in full compliance with the International Conference forHarmonization of Clinical Trials (ICH) and all applicable local GoodClinical Practices (GCP) and regulations.

Within the meaning of this invention, the term “healthy human subject”refers to a male or female subject with a body weight ranging from 55 kgto 100 kg and a body mass index (BMI) ranging from 18 to 29 and normalphysiological parameters, such as blood pressure, etc. Healthy humansubjects for the purposes of the present invention are selectedaccording to inclusion and exclusion criteria which are based on and inaccordance with recommendations of the ICH.

Within the meaning of this invention, the term “subject population”refers to at least ten individual healthy human subjects.

Within the meaning of this invention, the term “geometric mean” refersto the mean of the log transformed data back-transformed to the originalscale.

Within the meaning of this invention, the term “arithmetic mean” refersto the sum of all values of observation divided by the total number ofobservations.

Within the meaning of this invention, the parameter “AUC” corresponds tothe area under the plasma concentration-time curve. The AUC value isproportional to the amount of active agent absorbed into the bloodcirculation in total and is hence a measure for the bioavailability.

Within the meaning of this invention, the parameter “AUC_(t1-t2)” isprovided in (ng/ml) h and relates to the area under the plasmaconcentration-time curve from hour t1 to t2 and is calculated by thelinear trapezoidal method.

Within the meaning of this invention, the parameter “C_(max)” isprovided in (ng/ml) and relates to the maximum observed blood plasmaconcentration of the active agent.

Within the meaning of this invention, the parameter “C_(t)” is providedin (ng/ml) and relates to the blood plasma concentration of the activeagent observed at hour t.

Within the meaning of this invention, the parameter “t_(max)” isprovided in h and relates to the time point at which the C. value isreached. In other words, tmax is the time point of the maximum observedplasma concentration.

Within the meaning of this invention, the parameter “t_(lag)” isprovided in h and relates to the delay between the time ofadministration (in case of a TTS the time when the TTS is first appliedto the skin, i.e. t=0) and the time of appearance of measurable bloodplasma concentration. The t_(lag) can be calculated approximatively asthe mean arithmetic value of the first point in time when a measurable(i.e. non-zero) active agent blood plasma concentration is obtained orrepresented by a median value.

Within the meaning of this invention, the term “mean plasmaconcentration” is provided in (ng/ml) and is a mean of the individualplasma concentrations of active agent, e.g. asenapine, at each point intime.

Within the meaning of this invention, the term “coating composition”refers to a composition comprising all components of the matrix layer ina solvent, which may be coated onto the backing layer or release linerto form the matrix layer upon drying.

Within the meaning of this invention, the term “dissolve” refers to theprocess of obtaining a solution, which is clear and does not contain anyparticles, as visible to the naked eye.

Within the meaning of this invention, the term “solvent” refers to anyliquid substance, which preferably is a volatile organic liquid such asmethanol, ethanol, isopropanol, acetone, ethyl acetate, methylenechloride, hexane, n-heptane, heptanes, toluene and mixtures thereof.

Within the meaning of this invention, and unless otherwise specified,the term “about” refers to an amount that is ±10% of the disclosedamount. In some embodiments, the term “about” refers to an amount thatis ±5% of the disclosed amount. In some embodiments, the term “about”refers to an amount that is ±2% of the disclosed amount.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1a depicts the asenapine skin permeation rate of TTS preparedaccording to Reference Examples la to lc for hours 0 to 72.

FIG. 1b depicts the utilization of asenapine of TTS prepared accordingto Reference Examples 1 a to 1 c after 72 hours.

FIG. 2a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% relative humidity (RH) over 0 to 12 months for TTS preparedaccording to Example 2a and Reference Examples 2c and 2d.

FIG. 2b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH over 0 to 6 months for TTS prepared according to Example 2a andReference Examples 2c and 2d.

FIG. 3a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH over 0 to 3 months for TTS prepared according to Example 3a andover 0 to 2 months for TTS prepared according to Examples 3b and 3c.

FIG. 3b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH over 0 to 3 months for TTS prepared according to Example 3a andover 0 to 2 months for TTS prepared according to Examples 3b and 3c.

FIG. 3c depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 5° C. after4.5 months for a TTS prepared according to Example 2a, after 4 monthsfor a TTS prepared according to Example 2b, and after 2 months for TTSprepared according to Examples 3d and 3e.

FIG. 4a depicts the asenapine skin permeation rate of TTS preparedaccording to Examples 4a and 4b as well as Reference Example lc forhours 0 to 72.

FIG. 4b depicts the utilization of asenapine of TTS prepared accordingto Examples 4a and 4b as well as Reference Example lc after 72 hours.

FIG. 5a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH after 2.5 months for TTS prepared according to Reference Examples5a, 5b and 5c.

FIG. 5b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH after 12 months for TTS prepared according to Reference Examples5a and 5c.

FIG. 6a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH after 2.5 months for TTS prepared according to Reference Examples6a, 6b, 6c and 6d.

FIG. 6b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH after 12 months for TTS prepared according to Reference Examples6a, 6c and 6d.

FIG. 7a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH after 2.5 months for TTS prepared according to Reference Examples7a, 7b, 7c and 7d.

FIG. 7b depicts the sum of all related (i.e. possible degradationproduct) substances detected in an analysis of coating compositions(prior to coating) prepared according to Reference Examples 6a, 7a, 7b,7c and 7d.

FIG. 8a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH after 2.5 months for TTS prepared according to Examples 8a, 8b,8c, 8d and 8e.

FIG. 8b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH after 12 months for TTS prepared according to Examples 8a, 8b,8c, 8d and 8e.

FIG. 9a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH over 0 to 12 months for TTS prepared according to ReferenceExample 2d and Examples 9a, 9b and 9c.

FIG. 9b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 30° C. and75% RH over 0 to 12 months for TTS prepared according to Examples 9a, 9band 9c.

FIG. 9c depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH over 0 to 6 months for TTS prepared according to ReferenceExample 2d and Examples 9a, 9b and 9c.

FIG. 9d depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH over 0 to 12 months for TTS prepared according to ReferenceExample 2d and Examples 9a, 9d and 9e.

FIG. 9e depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 30° C. and75% RH over 0 to 12 months for TTS prepared according to Examples 9a, 9dand 9e.

FIG. 9f depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH over 0 to 6 months for TTS prepared according to ReferenceExample 2d and Examples 9a, 9d and 9e.

FIG. 10a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH over 0 to 12 months for TTS prepared according to ReferenceExample 2d and Examples 9a and 10 a and over 0 to 6 months for TTSprepared according to Example 10b.

FIG. 10b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 30° C. and75% RH over 0 to 12 months for TTS prepared according to Examples 9a and10 a and over 0 to 6 months for TTS prepared according to Example 10b.

FIG. 10c depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH over 0 to 6 months for TTS prepared according to ReferenceExample 2d and Examples 9a, l0a and 10b.

FIG. 11a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH initially and after 1 month for TTS prepared according to Example11a and Reference Examples 11c and 11d.

FIG. 11b depicts the amount of asenapine base detected in a storagestability test at 40° C. and 75% RH initially and after 1 month for TTSprepared according to Example 11a and Reference Examples 11c and 11d.

FIG. 11c depicts the asenapine skin permeation rate of TTS preparedaccording to Example 11 a and Reference Examples 11c and 11d for hours 0to 96.

FIG. 11d depicts the utilization of asenapine of TTS prepared accordingto Example 11 a and Reference Examples 11c and 11d after 72 hours.

FIG. 11e to 11g show pictures of the prepared TTS according to Example11 a (FIG. 11e ), Reference Example 11c (FIG. 11f ) and ReferenceExample 11d (FIG. 11g ).

FIG. 12a depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 25° C. and60% RH over 0 to 9 months for TTS prepared according to ReferenceExample 2d and over 0 to 6 months for Examples 12a, 12b and 12c.

FIG. 12b depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 30° C. and75% RH over 0 to 6 months for Examples 12a, 12b and 12c.

FIG. 12c depicts the sum of all related (i.e. possible degradationproduct) substances detected in a storage stability test at 40° C. and75% RH over 0 to 6 months for Reference Example 2d and Examples 12a, 12band 12c.

FIG. 12d depicts the amount of asenapine base detected in a storagestability test at 25° C. and 60% RH initially and after 3 months for TTSprepared according to Reference Example 2d and Examples 9a, 12a, 12b and12c, after 6 months for TTS prepared according to Examples 9a, 12a, 12band 12c, and after 9 months for TTS prepared according to ReferenceExample 2d and Example 9a.

FIG. 12e depicts the amount of asenapine base detected in a storagestability test at 30° C. and 75% RH initially, after 3 months and after6 months for TTS prepared according to Examples 9a, 12a, 12b and 12c.

FIG. 12f depicts the amount of asenapine base detected in a storagestability test at 40° C. and 75% RH initially, after 3 months and after6 months for TTS prepared according to

Reference Example 2d and Examples 9a, 12a, 12b and 12c.

FIG. 13a depicts the asenapine blood plasma concentration (arithmeticmean values with standard deviation as error bars) obtained in an invivo clinical study of the TTS prepared according to Reference Examples2c and 2d for hours 0 to 168.

FIG. 13b depicts the asenapine blood plasma concentration (arithmeticmean values with standard deviation as error bars) obtained in an invivo clinical study of the TTS prepared according to Reference Examples2c and 2d for hours 0 to 84.

FIG. 13c depicts the asenapine-glucuronide blood plasma concentration(geometric mean values with geometric mean multiplied with/divided bythe geometric standard deviation as error bars) obtained in an in vivoclinical study of the TTS prepared according to Reference Examples 2cand 2d for hours 0 to 168.

FIG. 13d depicts the asenapine-glucuronide blood plasma concentration(geometric mean values with geometric mean multiplied with/divided bythe geometric standard deviation as error bars) obtained in an in vivoclinical study of the TTS prepared according to Reference Examples 2cand 2d for hours 0 to 96.

FIG. 13e depicts the N-desmethyl-asenapine blood plasma concentration(geometric mean values with geometric mean multiplied with/divided bythe geometric standard deviation as error bars) obtained in an in vivoclinical study of the TTS prepared according to Reference Examples 2cand 2d for hours 0 to 108.

DETAILED DESCRIPTION TTS Structure

The present invention is related to a transdermal therapeutic system forthe transdermal administration of asenapine comprising a self-adhesivelayer structure containing asenapine.

The self-adhesive layer structure contains therapeutically effectiveamounts of asenapine and comprises A) a backing layer, and B) anasenapine-containing matrix layer consisting of a matrix layercomposition comprising 1. asenapine, 2. a polymer, 3. an additionalpolymer, and 4. α-tocopherol and ascorbyl palmitate as stabilizers.

Thus, the transdermal therapeutic system for the transdermaladministration of asenapine comprises a self-adhesive layer structurecontaining a therapeutically effective amount of asenapine, saidself-adhesive layer structure comprising:

A) a backing layer;

B) an asenapine-containing matrix layer consisting of a matrix layercomposition comprising:

-   -   1. asenapine;    -   2. a polymer selected from acrylic polymers;    -   3. an additional polymer; and    -   4. α-tocopherol in an amount of from 0.01 to 2% of the matrix        layer composition and ascorbyl palmitate in an amount of at        least 0.01% of the matrix layer composition as stabilizers.

The backing layer is in particular substantially asenapine-impermeable.

The TTS according to the present invention may be a matrix-type TTS or areservoir-type TTS, and preferably is a matrix-type TTS.

In such a matrix-type TTS, the asenapine, and preferably atherapeutically effective amount of asenapine, is included in theasenapine-containing matrix layer. The self-adhesive layer structure insuch a matrix-type TTS can include one or more further layers such as askin contact layer. In such a further layer, the active agent may beincluded or may not be included.

As outlined above, a skin contact layer can, even if manufactured as anactive agent-free layer, after equilibration, comprise asenapine andthen may also be regarded as a (further) matrix layer. The further layerand the asenapine-containing matrix layer may comprise the same polymeror different polymers. Any of the asenapine-containing matrix layer andthe further layer(s) may be directly contacting each other or separatedby a membrane such as a rate controlling membrane.

If an asenapine-containing layer is prepared by laminating twoasenapine-containing matrix layers, which are of substantially the samecomposition, the resulting double layer is to be regarded as one matrixlayer.

In certain embodiments, the self-adhesive layer structure comprises anadditional reservoir layer which is located between the backing layerand the matrix layer, and a further rate controlling membrane which islocated between the additional reservoir layer and the matrix layer.

In specific embodiments, the self-adhesive layer structure according tothe invention comprises an additional skin contact layer. The additionalskin contact layer is self-adhesive and provides for adhesion betweenthe self-adhesive layer structure and the skin of the patient duringadministration.

In such embodiments, the self-adhesive layer structure may or may notcomprise a membrane, which is located between the matrix layer and theadditional skin contact layer, wherein the membrane is preferably a ratecontrolling membrane.

In another embodiment, the self-adhesive layer structure according tothe invention does not comprise an additional skin contact layer.Sufficient adhesion between the self-adhesive layer structure and theskin of the patient during administration is then provided for by othermeans, e.g. an asenapine-containing matrix layer and/or an adhesivelayer.

Thus, according to certain embodiments of the invention, the TTS mayfurther comprise an adhesive overlay or does not comprise an adhesiveoverlay, and preferably does not comprise an adhesive overlay. Thisadhesive overlay is in particular larger than the asenapine-containingself-adhesive layer structure and is attached thereto for enhancing theadhesive properties of the overall transdermal therapeutic system. Saidadhesive overlay comprises also a backing layer. The area of saidadhesive overlay adds to the overall size of the TTS but does not add tothe area of release. The adhesive overlay comprises a self-adhesivepolymer or a self-adhesive polymer mixture selected from the group ofacrylic polymers, polyisobutylenes, styrene-isoprene-styrene copolymers,polysiloxanes, and mixtures thereof, which may be identical to ordifferent from any polymer or polymer mixture included in the activeagent-containing self-adhesive layer structure.

The self-adhesive layer structure according to the invention is normallylocated on a detachable protective layer (release liner) from which itis removed immediately before application to the surface of thepatient's skin. Thus, the TTS may further comprise a release liner. ATTS protected this way is usually stored in a seam-sealed pouch. Thepackaging may be child resistant and/or senior friendly.

Matrix Layer and Matrix Layer Composition

As outlined in more detail above, the TTS of the present inventioncomprises a self-adhesive layer structure comprising anasenapine-containing matrix layer consisting of a matrix layercomposition.

The matrix layer composition comprises:

-   -   1. asenapine;    -   2. a polymer selected from acrylic polymers;    -   3. an additional polymer; and    -   4. α-tocopherol in an amount of from 0.01 to 2% of the matrix        layer composition and ascorbyl palmitate in an amount of at        least 0.01% of the matrix layer composition as stabilizers.

In a specific embodiment of the invention, the matrix layer compositioncomprises asenapine and a polymer selected from acrylic polymers,wherein the transdermal therapeutic system has an area of release offrom 5 to 100 cm².

In certain embodiments of the invention, the area of release ranges from5 to 100 cm², preferably from 5 to 80 cm², and more preferably from 10to 50 cm² or from 50 to 80 cm², from 10 to 40 cm² or from 10 to 30 cm²or from 55 to 65 cm², i.e. the transdermal therapeutic system has anarea of release of from 5 to 100 cm², preferably from 5 to 80 cm², andmore preferably from 10 to 50 cm² or from 50 to 80 cm², from 10 to 40cm² or from 10 to 30 cm² or from 55 to 65 cm².

In certain embodiments of the invention, the area weight of the matrixlayer ranges from 90 to 230 g/m², preferably from 110 to 210 g/m², andmost preferably from 120 to 170 g/m².

Without wishing to be bound by theory, it is believed that the good invitro skin permeation is inter alia achieved by the amount of asenapinecontained in the TTS, which can be controlled two-way by adjustingconcentration and/or the area weight of the asenapine-containing layerssuch as the matrix layer.

Thus, in certain embodiments of the invention, the transdermaltherapeutic system contains at least 0.70 mg/cm², preferably at least0.80 mg/cm², more preferably at least 0.82 mg/cm² and most preferably atleast 0.83 mg/cm² asenapine per area of release. In certain furtherembodiments of the invention, the transdermal therapeutic systemcontains at least 0.90 mg/cm², at least 1.00 mg/cm², at least 1.2mg/cm², at least 1.5 mg/cm² or at least 2.0 mg/cm² asenapine per area ofrelease.

In particular, the transdermal therapeutic system contains from 0.70mg/cm² to 4.0 mg/cm², preferably from 0.80 mg/cm² to 3.0 mg/cm², morepreferably from 0.82 mg/cm² to 2.0 mg/cm² and most preferably from 0.83mg/cm² to 1.7 mg/cm² asenapine.

In certain embodiments of the invention, the matrix layer composition isa pressure-sensitive adhesive composition. The matrix layer compositionmay comprise a second polymer or may comprise two or more furtherpolymers.

According to certain embodiments of the invention, the total polymercontent in the matrix layer composition ranges from 60 to 95%,preferably from 70 to 90% and more preferably from 75 to 85% of thematrix layer composition. In any event does the matrix layer includesufficient amounts of polymer to provide sufficient cohesion.

According to certain embodiments, the amount of asenapine contained inthe TTS, in particular in the matrix layer of the TTS, ranges from 5 to100 mg, preferably from 10 to 80 mg, and most preferably from 15 to 60mg.

In certain embodiments, the transdermal therapeutic system has an areaof release of from 5 to 100 cm², and the amount of asenapine containedin the TTS ranges from 5 to 100 mg.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise isopropyl palmitate in an amount of 10% of thematrix layer composition, preferably does not comprise isopropylpalmitate in an amount of 5-15% of the matrix layer composition and mostpreferably does not comprise isopropyl palmitate.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise isopropyl myristate in an amount of 5% of thematrix layer composition, preferably does not comprise isopropylmyristate in an amount of 1-10% of the matrix layer composition and mostpreferably does not comprise isopropyl myristate.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise ethyl cellulose in an amount of 10-20% of thematrix layer composition and preferably does not comprise ethylcellulose.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise hydrogen chloride.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise sodium acetate or sodium diacetate. In yetanother embodiment, the asenapine-containing layer does not comprise adicarboxylic acid alkali salt. In yet another embodiment, theasenapine-containing layer does not comprise a maleic acid alkali salt.

In certain embodiments of the invention, the matrix layer compositiondoes not comprise any of polysiloxanes and polyisobutylenes in an amountof more than 50% of the matrix layer composition.

In certain embodiments, the asenapine-containing matrix layer isobtainable by drying a coated coating composition wherein nohydrochloric acid has been included in the coating composition.

In certain embodiments of the invention, the asenapine-containing matrixlayer does not comprise toluene.

In certain embodiments of the invention, the asenapine-containing matrixlayer is obtainable by drying a coated coating composition comprising notoluene.

Asenapine

In accordance with the invention, the self-adhesive layer structurecontains asenapine in a therapeutically effective amount, and theself-adhesive layer structure comprises an asenapine-containing matrixlayer consisting of a matrix layer composition comprising asenapine.

While in accordance with the present invention, the active agent may bepresent in the TTS in protonated or in free base form, the free baseform is preferred.

Thus, in certain embodiments, the asenapine in the matrix layercomposition is included in the form of the free base.

In certain embodiments, the matrix layer composition is obtainable byincorporating the asenapine in the form of the free base.

In particular, at least 90 mol %, preferably at least 95 mol %, morepreferably at least 98 mol % and most preferably at least 99 mol % ofthe asenapine in the matrix layer is present in the form of the freebase.

The asenapine in the matrix layer may be completely dissolved, or thematrix layer composition may contain asenapine particles, preferablyconstituted of asenapine free base.

As outlined above, the amount of asenapine in the TTS is believed to beimportant for a good release of the active, and can be e.g. adjusted bythe asenapine concentration. Thus, in certain embodiments, the amount ofasenapine in the matrix layer composition ranges from 2 to 20%,preferably from 3 to 15% and more preferably from 4 to 12% of the matrixlayer composition.

In certain embodiments, the asenapine has a purity of at least 95%,preferably of at least 98% and more preferably of at least 99% asdetermined by quantitative HPLC. Quantitative HPLC may be performed withReversed-Phase-HPLC with UV detection. In particular, the followingconditions can be used if HPLC is performed isocratically:

Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1) Kromasil C18125 mm × 4.0 mm; 5 μm or equivalent Mobile phase: 0.05 molar KH₂PO₄Buffer/Methanol/TEA (45:55:0.1; v:v:v); pH 2.5 ± 0.05 (TEA =triethylamine) Gradient: isocratic Flux: 1.0 ml Injection volume: 30 μlColumn temperature:. 40° C. Wavelength: 225 nm, 270 nm and 3-D-field;Evaluation is performed at 270 nm Run time: 10 min Furthermore, thefollowing conditions can be used if HPLC is performed with a gradient:Column: Octadecyl phase acc. Ph. Eur. 2.2.29 (USP phase L1) Kinetex C18EVO 100 mm × 4.6 mm; 2.1 μm or equivalent Mobile phase: A: 0.02 molarKH₂PO₄ Buffer/Methanol/TEA (70:30:0.1; v:v:v) adj. to pH 2.5 B: 0.02molar KH₂PO₄ Buffer/Methanol/TEA (30:70:0.1; v:v:v); adj. to pH 2.5 (TEA= triethylamine) Flux: 0.7 ml Injection volume: 30 μl Columntemperature: 40° C. Wavelength: 225 nm, 270 nm and 3-D-field; Evaluationis performed at 225 nm Run time: 32 min Gradient profile:  0.00 min: A:100% B: 0% 12.00 min: A: 40% B: 60% 18.00 min: A: 0% B: 100% 27.00 min:A: 0% B: 100% 27.01 min: A: 100% B: 0% 32.00 min: A: 100% B: 0%

Polymer

As outlined above, the TTS according to the present invention comprisesa self-adhesive layer structure comprising an asenapine-containingmatrix layer consisting of a matrix layer composition, wherein thematrix layer composition comprises a polymer.

This polymer provides for sufficient cohesion of the matrix layer.According to certain embodiments the polymer may also provide forsufficient adhesion. In those embodiments the polymer is selected frompressure sensitive adhesive polymers.

In a preferred embodiment, the polymer is selected frompressure-sensitive adhesive polymers.

Polymers which are suitable as the polymer in accordance with theinvention are acrylic polymers.

Corresponding commercial products are available e.g. under the brandname Duro-Tak™ (see below for details).

The acrylic polymers comprise or do not comprise functional groups.

Corresponding commercial products are available e.g. under the brandnames Duro-Tak™ 387-2287 (an acrylic copolymer comprising hydroxylgroups), Duro-Tak™ 87-4287 (an acrylic copolymer comprising hydroxylgroups), Duro-Tak™ 387-2516 (an acrylic copolymer comprising hydroxylgroups), Duro-Tak™ 387-2051 (an acrylic copolymer comprising carboxylicacid groups), Duro-Tak™ 387-2353 (an acrylic copolymer comprisingcarboxylic acid groups), Duro-Tak™ 387-4098 (an acrylic copolymercomprising no functional groups) and Duro-Tak™ 387-9301 (an acryliccopolymer comprising no functional groups).

In certain embodiments, the polymer is selected from acrylic polymerscomprising functional groups wherein the functional groups are selectedfrom hydroxyl groups, carboxylic acid groups, neutralized carboxylicacid groups and mixtures thereof. Preferably, the functional groups arelimited to hydroxyl groups.

In certain embodiments, the polymer is selected from acrylic polymers,which do not comprise carboxylic acid groups or neutralized carboxylicacid groups or both groups, and preferably the polymer is selected fromacrylic polymers which do not comprise acidic groups.

In further preferred embodiments, the polymer is selected from acrylicpolymers comprising hydroxyl groups and no carboxylic acid groups, andmore preferably, the polymer is a copolymer based on vinyl acetate,2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylateor a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate and2-hydroxyethyl-acrylate.

Such a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate,2-hydroxyethyl-acrylate and glycidyl-methacrylate is commerciallyavailable under the brand names Duro-Tak™ 387-2287 (provided as asolution in ethyl acetate without cross-linking agent) and Duro-Tak™387-2516 (provided as a solution in ethyl acetate, ethanol, heptanes andmethanol with a titanium cross-linking agent). A copolymer based onvinyl acetate, 2-ethylhexyl-acrylate and 2-hydroxyethyl-acrylate(provided as a solution in ethyl acetate without cross-linking agent) iscommercially available under the brand name Duro-Tak™ 387-4287. Thus,depending on the type of commercially available acrylic polymer used anddepending on whether a cross-linking agent is added to the coatingcomposition, the polymer in the finalized matrix layer is cross-linked(and preferably is cross-linked by an aluminium and/or a titaniumcross-linking agent) or is not cross-linked by a cross-linking agent.

In certain other embodiments, the polymer is selected from acrylicpolymers comprising no hydroxyl groups and no carboxylic acid groups,and preferably, the polymer is selected from acrylic polymers comprisingno functional groups.

In further preferred embodiments, the polymer is a copolymer based onmethyl acrylate, 2-ethylhexyl acrylate and t-octyl acrylamide, and whichis commercially available under the brand name Duro-Tak™ 387-9301(provided as a solution in ethyl acetate).

In further preferred embodiments, the polymer is a copolymer based on2-ethylhexyl-acrylate and vinyl acetate, which is commercially availableunder the brand name Duro-Tak™ 387-4098 (provided as a solution in ethylacetate).

In certain preferred embodiments, the amount of the polymer ranges from50 to 90%, preferably from 60 to 85% and more preferably from 65 to 80%of the matrix layer composition.

Additional Polymer

As outlined above, in the TTS according to the present invention, thematrix layer composition comprises an additional polymer.

Of particular interests are polymers with an enhanced ability to absorbwater, as higher water and/or moisture absorption assists inmaintaining/improving the adhesive properties of the matrix layer.

Thus, in certain embodiments, the matrix layer composition comprises anadditional polymer selected from polymers, which provide for an improvedwater and/or moisture absorption of the matrix layer. Such polymers arewell known in the art. Of those, particularly suitable and preferred arepolyvinylpyrrolidones, and in particular soluble polyvinylpyrrolidones.

The term “soluble polyvinylpyrrolidone” refers to polyvinylpyrrolidone,also known as povidone, which is soluble with more than 10% in at leastethanol, preferably also in water, diethylene glycol, methanol,n-propanol, 2-propanol, n-butanol, chloroform, methylene chloride,2-pyrrolidone, macrogol 400, 1,2 propylene glycol, 1,4 butanediol,glycerol, triethanolamine, propionic acid and acetic acid. Examples ofpolyvinylpyrrolidones which are commercially available include Kollidon®12 PF, Kollidon® 17 PF, Kollidon® 25, Kollidon® 30 and Kollidon® 90 Fsupplied by BASF, or povidone K9OF. The different grades of Kollidon®are defined in terms of the K-Value reflecting the average molecularweight of the polyvinylpyrrolidone grades. Kollidon® 12 PF ischaracterized by a K-Value range of 10.2 to 13.8, corresponding to anominal K-Value of 12. Kollidon® 17 PF is characterized by a K-Valuerange of 15.3 to 18.4, corresponding to a nominal K-Value of 17.Kollidon® 25 is characterized by a K-Value range of 22.5 to 27.0,corresponding to a nominal K-Value of 25, Kollidon® 30 is characterizedby a K-Value range of 27.0 to 32.4, corresponding to a nominal K-Valueof 30. Kollidon® 90 F is characterized by a K-Value range of 81.0 to97.2, corresponding to a nominal K-Value of 90. Preferred Kollidon®grades are Kollidon® 12 PF, Kollidon® 30 and Kollidon® 90 F. For allgrades and types of polyvinylpyrrolidone, it is preferred that theamount of peroxides is within certain limits, in particular, theperoxide amount is equal to or less than 500 ppm, more preferably equalto or less than 150 ppm, and most preferably equal to or less than 100ppm.

Within the meaning of this invention, the term “K-Value” refers to avalue calculated from the relative viscosity of polyvinylpyrrolidone inwater according to the European Pharmacopoeia (Ph.Eur.) and USPmonographs for “Povidone”.

Thus, in certain embodiments, the matrix layer composition comprises anadditional polymer, wherein the additional polymer is apolyvinylpyrrolidone having a K-Value within a range selected from thegroup of ranges consisting of

-   9 to 15, and preferably 10.2 to 13.8,-   15 to 20, and preferably 15.3 to 18.4,-   20 to 27, and preferably 22.5 to 27.0,-   27 to 35, and preferably 27.0 to 32.4, and-   75 to 110, and preferably 81.0 to 97.2,    or any mixtures thereof, and more preferably is a    polyvinylpyrrolidone having a K-Value within a range of 27.0 to 32.4    or of 81.0 to 97.2, and any mixtures thereof, and most preferably is    a polyvinylpyrrolidone having a K-Value within range of 27.0 to    32.4.

The additional polymer, e.g. polyvinylpyrrolidones, and preferablysoluble polyvinylpyrrolidones, may be present for example in an amountof from 0 to 20% of the matrix layer composition, preferably of from 5to 15% of the matrix layer composition and more preferably in an amountof about 10% of the matrix layer composition.

The matrix layer composition may e.g. comprise one of the aforementionedpolymers as additional polymer(s). Other additional polymers andadditives may also be added to enhance cohesion and/or adhesion.

Other polymers in particular reduce the cold flow and are thus alsosuitable as additional polymer. A polymeric matrix may show a cold flow,since such polymer compositions often exhibit, despite a very highviscosity, the ability to flow very slowly. Thus, during storage, thematrix may flow to a certain extent over the edges of the backing layer.This is a problem with storage stability and can be prohibited by theaddition of certain polymers. A basic acrylate polymer (e.g. EudragitE100 which is a copolymer based on dimethylaminoethyl methacrylate,butyl methacrylate and methyl methacrylate) may e.g. be used to reducethe cold flow. Thus, in certain embodiments, the matrix layercomposition comprises additionally a basic polymer, in particular anamine-functional acrylate as e.g. Eudragit E100.

According to certain embodiments, the total polymer content in thematrix layer composition ranges from 60 to 95%, preferably from 70 to90% and more preferably from 75 to 85% of the matrix layer composition.

Stabilizers

As outlined above, the TTS according to the present invention comprisesa self-adhesive layer structure comprising an asenapine-containingmatrix layer consisting of a matrix layer composition, wherein thematrix layer composition comprises α-tocopherol and ascorbyl palmitate.

The α-tocopherol and ascorbyl palmitate are included as stabilizers. Theinventors have surprisingly found that the stability of the inventiveformulations in terms of asenapine content and degradation is improvedby a synergistic combination of α-tocopherol and ascorbyl palmitate, inparticular in certain specific amounts.

Thus, the matrix layer composition comprises α-tocopherol in an amountof from 0.01 to 2% of the matrix layer composition and ascorbylpalmitate in an amount of at least 0.01% of the matrix layer compositionas stabilizers.

The inventors have further found that the advantageous effect onstability can be further improved by addition of sodium metabisulfite.Thus, preferably, the matrix layer composition further comprises sodiummetabisulfite in an amount of from 0 to 0.5%, preferably from 0.01 to0.2%, and more preferably from 0.05 to 0.15% of the matrix layercomposition as stabilizer. Particularly preferably, the matrix layercomposition further comprises sodium metabisulfite in an amount of about0.1% of the matrix layer composition as stabilizer. Where the presentapplication is referring to sodium metabisulfite, any other sulfite ordisulfite is considered to be included as an alternative embodiment.

In terms of the amount of α-tocopherol and ascorbyl palmitate, certainranges have a particularly favorable effect on the stability.

Thus, the matrix layer composition preferably comprises α-tocopherol atleast 0.025% of the matrix layer composition, and/or in an amount of upto 1.5% or 0.75%, preferably up to 0.5%, and more preferably up to 0.1%of the matrix layer composition, and most preferably in an amount ofabout 0.05% of the matrix layer composition.

The matrix layer composition may further comprise ascorbyl palmitate inan amount of at least 0.02% of the matrix layer composition, preferablyat least 0.08% of the matrix layer composition, and more preferably atleast 0.15% of the matrix layer composition, and/or in an amount of upto 2.0 or 1.0%, preferably up to 0.6% of the matrix layer composition,and more preferably in an amount of from 0.2 to 0.4% of the matrix layercomposition.

In certain embodiments, the matrix layer composition may comprise one ormore further stabilizers selected from ascorbic acid and esterderivatives thereof, butylated hydroxytoluene, tocopherol esterderivatives such as tocopheryl acetate and tocopheryl linoleate,carboxylic acids, and in particular branched or linear alkyl mono-, di-or tri-carboxylic acids, preferably a branched or linear C4 toC16-monocarboxylic acid and more preferably isononanoic acid orheptanoic acid, and most preferably 3,5,5-trimethylhexanoic acid, aswell as any combination thereof.

The TTS according to the present invention advantageously show animproved stability in terms of the asenapine content as well asasenapine degradation.

Thus, in certain embodiments, the matrix layer contains initially (i.e.shortly after manufacture e.g. within one week) an amount of asenapineof at least 95%, preferably of at least 96%, more preferably of at least97% and even more preferably of at least 98% of the theoretical amountof asenapine included in the matrix layer. The theoretical amount ofasenapine is calculated from the asenapine amount used for the coatingcomposition and the (actual) area weight of the coated and dried matrixlayer of the tested TTS.

The matrix layer may also contain initially a total amount ofasenapine-related degradation substances of less than 0.7%, preferablyof less than 0.5%, more preferably of less than 0.3% and even morepreferably of less than 0.2%.

In certain other embodiments, the TTS according to the present inventionare stable upon storage, i.e. they may maintain the initial asenapinecontent values or present low amounts of degradation products, asfollows:

In one of such embodiments, the matrix layer contains, after having beenstored at 25° C. and 60% relative humidity for at least 2 months,preferably at least 3 months, an amount of asenapine of at least 90%,preferably of at least 92%, more preferably of at least 94% and evenmore preferably of at least 95% of the theoretical amount of asenapineincluded in the matrix layer.

The matrix layer may also contain, after having been stored at 25° C.and 60% relative humidity for at least 2 months, preferably at least 3months, a total amount of asenapine-related degradation substances ofless than 1.0%, preferably of less than 0.7%, more preferably of lessthan 0.5% and even more preferably of less than 0.4%.

In another of such embodiments the matrix layer contains, after havingbeen stored at 40° C. and 75% relative humidity for at least 2 months,preferably at least 3 months, an amount of asenapine of at least 88%,preferably of at least 90%, more preferably of at least 91% and evenmore preferably of at least 92% of the theoretical amount of asenapineincluded in the matrix layer.

The matrix layer may also contain, after having been stored at 40° C.and 75% relative humidity for at least 2 months, preferably at least 3months, a total amount of asenapine-related degradation substances ofless than 3.0%, preferably of less than 2.0%, more preferably of lessthan 1.5% and even more preferably of less than 0.7%.

For determining the asenapine content and the total amount ofasenapine-related degradation substances, a TTS sample is extracted withan appropriate extraction solvent and the amount of asenapine base, aswell as various possible degradation substances is determined by aquantitative HPLC method with a UV photometric detector. The amount ofasenapine is determined based on an asenapine standard. The total amountof asenapine-related degradation substances (expressed in %) is the sumof the peak areas of all degradation substances, each multiplied by aresponse factor, which is 0.33 for tetradehydro asenapine and is 1 forall other substances, divided by the peak area of asenapine of thetested sample, and multiplied by 100%.

Further Additives

The matrix layer composition of the TTS according to the invention maycomprise further excipients or additives selected from the groupconsisting of additional polymers (see above), cross-linking agents,solubilizers, fillers, tackifiers, plasticizers, stabilizers, softeners,substances for skincare, permeation enhancers, i.e. substances whichinfluence the barrier properties of the stratum corneum in the sense ofincreasing the active agent permeability, pH regulators, andpreservatives. Particularly preferred additives are tackifiers andstabilizers. Such additives may be present in the asenapine-containinglayer in an amount of from 0.001% to 15% of the matrix layer compositionper additive. In a certain embodiment, the total amount of all additivesis from 0.001% to 25% of the matrix layer composition. Hereinafter,where a range for an amount of a specific additive is given, such arange refers to the amount per individual additive.

It should be noted that in pharmaceutical formulations, the formulationcomponents are categorized according to their physicochemical andphysiological properties, and in accordance with their function. Thismeans in particular that a substance or a compound falling into onecategory is not excluded from falling into another category offormulation component. E.g. a certain polymer can be a crystallizationinhibitor but also a tackifier. Some substances may e.g. be a typicalsoftener but at the same time act as a permeation enhancer. The skilledperson is able to determine based on his general knowledge in whichcategory or categories of formulation component a certain substance orcompound belongs to. In the following, details on the excipients andadditives are provided which are, however, not to be understood as beingexclusive. Other substances not explicitly listed in the presentdescription may be as well used in accordance with the presentinvention, and substances and/or compounds explicitly listed for onecategory of formulation component are not excluded from being used asanother formulation component in the sense of the present invention.

The cross-linking agent may be selected from the group consisting ofaluminium and titanium cross-linking agents such as aluminiumacetylacetonate, titanium acetylacetonate or polybutyltitanate, andpreferably is a titanium cross-linking agent. The amount ofcross-linking agent may range from 0.005 to 1%, and preferably from 0.01to 0.1% of the matrix layer composition. The matrix layer compositionmay also comprise a polymer which is self-crosslinking, i.e. comprises across-linking functional group such as glycidyl groups, which reactsupon heating. According to a further specific embodiment, the matrixlayer composition comprises a cross-linking agent as above and aself-crosslinking polymer.

In one embodiment, the matrix layer composition further comprises asolubilizer. The solubilizer preferably improves the solubility of theasenapine in the asenapine-containing layer.

Preferred solubilizers include, e.g., glycerol-, polyglycerol-,propylene glycol- and polyoxyethylene-esters of medium chain and/or longchain fatty acids, such as glyceryl mono linoleate, medium chainglycerides and medium chain triglycerides, non-ionic solubilizers madeby reacting castor oil with ethylene oxide, and any mixtures thereofwhich may further contain fatty acids or fatty alcohols; cellulose andmethylcellulose and derivatives thereof such as hydroxypropylcelluloseand hypromellose acetate succinate; various cyclodextrins andderivatives thereof; non-ionic tri-block copolymers having a centralhydrophobic chain of polyoxypropylene flanked by two hydrophilic chainsof polyoxyethylene known as poloxamers;a polyethylene glycol, polyvinylacetate and polyvinylcaprolactame-based graft copolymer, alsoabbreviated as PVAc-PVCap-PEG and known as Soluplus®; purified grades ofnaturally derived castor oil, of polyethylene glycol 400, ofpolyoxyethylene sorbitan monooleate (such as polysorbate 80) or ofpropylene glycols; diethylene glycol monoethyl ether; as well as any ofthe below mentioned soluble polyvinylpyrrolidones but alsoinsoluble/cross-linked polyvinylpyrrolidones also known as crospovidonessuch as Kollidon® CL, Kollidon® CL-M and Kollidon® CL-SF, andpolyvinylpyrrolidone-polyvinyl acetate copolymers, also known ascopovidones, such as Kollidon® VA64.

However, also the permeation enhancers mentioned below can act assolubilizers. Furthermore, also crystallization inhibitors may act assolubilizers.

Fillers such as silica gels, titanium dioxide and zinc oxide may be usedin conjunction with the polymer in order to influence certain physicalparameters, such as cohesion and bond strength, in the desired way.

In case the matrix layer is required to have self-adhesive propertiesand one or more polymers is/are selected which does/do not providesufficient self-adhesive properties, a tackifier is added. The tackifiermay be selected from triglycerides, polyethylene glycols, dipropyleneglycol, resins, resin esters, terpenes and derivatives thereof, ethylenevinyl acetate adhesives, dimethylpolysiloxanes and polybutenes, andmixtures thereof. In certain embodiments, the matrix layer compositioncomprises a tackifier in an amount of from 5 to 15% of the matrix layercomposition.

In certain embodiments, the matrix layer composition comprises mediumchain triglycerides. Such medium chain triglycerides are included as atackifier and provide for improved adhesion of the matrix layer to theskin. In certain embodiments, a sufficient amount of medium chaintriglycerides can be added to asenapine-containing matrix layercompositions comprising acrylic polymers without impairing the skinpermeation performance.

In such embodiments, the matrix layer composition may comprise mediumchain triglycerides in an amount of from 0.1 to 14% of the matrix layercomposition, preferably from 1 to 13% of the matrix layer composition,more preferably from 3 to 12% of the matrix layer composition, even morepreferably from 5 to 12% of the matrix layer composition, and mostpreferably in an amount of about 10% of the matrix layer composition. Interms of adhesion, high amounts of medium chain triglycerides arepreferable, but the cohesive properties may become insufficient at toohigh concentrations.

Medium chain triglycerides are esters derived from glycerol and threemedium chain fatty acids. The properties of triglycerides depend on thefatty acid composition, i.e. the composition based on all fattyacid-derived moieties present in the medium chain triglycerides (whichmeans that the fatty acid composition of 3 molecules of triglyceridesbased on one octanoid acid, one decanoic acid and one dodecanoic acideach is the same as the fatty acid composition of a mixture of a firsttriglyceride based only on octanoic acid, a second triglyceride basedonly on decanoic acid, and a third triglyceride based only on dodecanoicacid).

In certain embodiments, the fatty acid composition of the medium chaintriglycerides consists of one or more of

-   -   (i) Hexanoic acid,    -   (ii) Octanoic acid,    -   (iii) Decanoic acid,    -   (iv) Dodecanoic acid, and    -   (v) Tetradecanoic acid.

In certain preferred embodiments, the fatty acid composition of themedium chain triglycerides consists of

-   -   (i) 0 to 5% hexanoic acid,    -   (ii) 40.0 to 90.0% octanoic acid,    -   (iii) 10.0 to 55.0% decanoic acid,    -   (iv) 0 to 5% dodecanoic acid, and    -   (v) 0 to 2% tetradecanoic acid.

Preferably, the fatty acid composition of the medium chain triglyceridesconsists of

-   -   (i) 0 to 2% hexanoic acid,    -   (ii) 50.0 to 80.0% octanoic acid,    -   (iii) 20.0 to 45.0% decanoic acid,    -   (iv) 0 to 2% dodecanoic acid, and    -   (v) 0 to 1% tetradecanoic acid.

In certain of the above embodiments, the fatty acid composition of themedium chain triglycerides consists of

-   -   (i) 0 to 2% hexanoic acid,    -   (ii) 50.0 to 65.0% octanoic acid,    -   (iii) 30.0 to 45.0% decanoic acid,    -   (iv) 0 to 2% dodecanoic acid, and    -   (v) 0 to 1% tetradecanoic acid,

In certain other of the above embodiments, the fatty acid composition ofthe medium chain triglycerides consists of

-   -   (i) 0 to 2% hexanoic acid,    -   (ii) 65.0 to 80.0% octanoic acid,    -   (iii) 20.0 to 35.0% decanoic acid,    -   (iv) 0 to 2% dodecanoic acid, and    -   (v) 0 to 1% tetradecanoic acid.

The medium chain triglycerides further may present certain acid values,peroxide values and/or hydroxyl values.

I.e., in certain embodiments, the acid value of the medium chaintriglycerides is 0.5 mg KOH/g or less, preferably 0.2 mg KOH/g or lessand most preferably 0.1 mg KOH/g or less.

In certain other embodiments, the peroxide value of the medium chaintriglycerides is 5.0 mequi O/kg or less, preferably 2.0 mequi O/kg orless and most preferably 1.0 mequi O/kg or less.

In yet other embodiments, the hydroxyl value of the medium chaintriglycerides is 10 mg KOH/g or less, preferably 8.0 mg KOH/g or lessand most preferably 5.0 mg KOH/g or less.

In one embodiment, the matrix layer composition further comprises asoftener/plasticizer. Exemplary softeners/plasticizers include linear orbranched, saturated or unsaturated alcohols having 6 to 20 carbon atoms,triglycerides and polyethylene glycols.

In certain embodiments, the matrix layer composition comprises apermeation enhancer selected from diethylene glycol monoethyl ether,diisopropyl adipate, isopropyl myristate, isopropyl palmitate, lauryllactate, dimethylpropylene urea and a mixture of propylene glycolmonoesters and diesters of fatty acids. Such a mixture of propyleneglycol monoesters and diesters of fatty acids is commercially availablee.g. under the brand name Capryol, which is a propylene glycolmonocaprylate (type II), a mixture of propylene glycol monoesters anddiesters of fatty acids with a ratio of >90% monoesters and <10%diesters, wherein the fatty acids mainly consist of caprylic acid.

In certain other embodiments, the matrix layer composition does notcomprise a permeation enhancer selected from oleic acids, oleicalcohols, and mixtures thereof, and in particular the matrix layercomposition does not comprise a permeation enhancer at all. In anotherembodiment, the matrix layer composition does not comprise sodiumacetate or sodium diacetate. In yet another embodiment, theasenapine-containing layer does not comprise a dicarboxylic acid alkalisalt. In yet another embodiment, the matrix layer composition does notcomprise a maleic acid alkali salt.

The matrix layer composition according to the invention may comprise apH regulator. Preferably, the pH regulator is selected from aminederivatives, inorganic alkali derivatives, polymers with basic andacidic functionality, respectively.

Release Characteristics

The TTS in accordance with the invention are designed for transdermallyadministering asenapine to the systemic circulation for a predefinedextended period of time.

In one aspect, the TTS according to the invention provide a mean releaserate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h, preferably of1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000 μg/day, 1,000 to15,000 μg/24 h, 0.042 to 0.625 mg/h or 42 to 625 μg/h, and morepreferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h, 2,000 to 10,000μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417 mg/h or 83 to 417 μg/hover at least 24 hours of administration, preferably over at least 48hours of administration, more preferably over at least 72 hours ofadministration, and most preferably over at least 84 hours ofadministration.

According to certain embodiments, the TTS according to the inventionprovide a cumulative skin permeation rate of asenapine at hour 48 or athour 72 as measured in a Franz diffusion cell with dermatomed human skinof 1 μg/(cm² h) to 20 μg/(cm² h), preferably of 2 μg/(cm² h) to 15μg/(cm² h) and more preferably of 4 μg/(cm² h) to 12 μg/(cm² h).

In specific embodiments of the invention, the TTS according to theinvention as described above provides a skin permeation rate ofasenapine as measured in a Franz diffusion cell with dermatomed humanskin of

0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,

2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,

3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48,

2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72.

In certain embodiments, the transdermal therapeutic system according tothe invention provides a cumulative permeated amount of asenapine asmeasured in a Franz diffusion cell with dermatomed human skin of 0.05mg/cm² to 1.0 mg/cm², preferably of 0.1 mg/cm² to 0.7 mg/cm² over a timeperiod of 48 hours.

In certain embodiments, the transdermal therapeutic system according tothe invention provides a cumulative permeated amount of asenapine asmeasured in a Franz diffusion cell with dermatomed human skin of 0.1mg/cm² to 2.0 mg/cm², preferably 0.2 mg/cm² to 1.0 mg/cm² over a timeperiod of 72 hours.

Method of Treatment/Medical Use

In accordance with a specific aspect of the present invention, the TTSaccording to the invention is for use in a method of treatment, and inparticular in a method of treating a human patient.

In certain embodiments, the TTS according to the invention is preferablyfor use in a method of treating psychosis, and more preferably for usein a method of treating one or more conditions selected fromschizophrenia, bipolar disorder, posttraumatic stress disorder, majordepressive disorder, dementia related psychosis, agitation and manicdisorder, in particular for use in a method of treating schizophreniaand/or bipolar disorder in a human patient, and in particular for use ina method of treating acute manic or mixed episodes of bipolar disorderin a human patient.

In certain embodiments, the TTS according to the invention is for use ina method of treating acute manic or mixed episodes of bipolar disorderin an adult or a pediatric patient 10 to 17 years of age. In certainembodiments, the TTS according to the invention is for use as anadjunctive treatment to lithium or valproate in a method of treatingbipolar disorder in a human patient, in particular an adult. In certainembodiments, the TTS according to the invention is for use as amaintenance monotherapy treatment in a method of treating bipolardisorder in a human patient, in particular an adult.

The TTS may be further for use in a method of treatment with a dosinginterval of at least 24 hours or 1 day, at least 48 hours or 2 days, orat least 72 hours or 3 days, and/or with a dosing interval of up to 168hours or 7 days, up to 120 hours or 5 days, or up to 96 hours or 4 days.The dosing interval may in particular be 24 hours or 1 day, 48 hours or2 days, or 84 hours or 3.5 days.

Accordingly the invention is also related to TTS for use in a method oftreatment, and in particular for use in a method of treatingschizophrenia and/or bipolar disorder, and in particular acute manic ormixed episodes of bipolar disorder, in an around-the-clock treatmentwith a once-a-day TTS exchange mode (dosing interval of 24 hours or 1day), a twice-a-week TTS exchange mode (dosing interval of 84 hours or3.5 days) or a once-a-week TTS exchange mode (dosing interval of 168hours, or 7 days).

The TTS according to the invention is further preferably for use in amethod of treating a patient, wherein the transdermal therapeutic systemprovides a reduction in at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine.

Relative to an equivalent dose of sublingual asenapine should beunderstood as a comparison in the incidence and intensity of sideeffects in a clinical study when using a dose of transdermal andsublingual asenapine that leads substantially to the same blood plasmaexposure of asenapine.

In another embodiment, the TTS according to the invention may also befor use in a method of reducing, in a patient, at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine.

In such a method of treating a patient or in such a method of reducingat least one asenapine-related side effect, but also in all thetransdermal therapeutic systems for use in a method of treatment, thetransdermal therapeutic systems for use in a method of reducing at leastone asenapine-related side effect as well as the methods of treatmentand methods of reducing at least one asenapine-related side effect, thefollowing may generally further apply:

(i) The at least one asenapine-related side effect is in particularfatigue, somnolence, dizziness, oral hypoaesthesia, or any combinationthereof.

(ii) As these side effects are reduced, in one embodiment, the inventivemethods and transdermal therapeutic systems for use in the methods arein particular suitable for a human patient already suffering from such acondition, i.e. suffering from fatigue, somnolence, dizziness, or anycombination thereof.

(iii) Further, the incidence of the at least one asenapine-related sideeffect relative to an equivalent dose of sublingual asenapine may bereduced by at least about 30%, at least about 40%, at least about 70% orat least about 80%, and/or the intensity of the at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine may be reduced. The intensity of a side effect canbe determined e.g. by classifying the side effects on a scale indicating“mild”, “moderate” or “severe” intensity, and a reduction of theintensity can be quantified by comparing the median intensity.

(iv) In such embodiments, the at least one asenapine-related side effectmay be fatigue and the incidence of fatigue relative to an equivalentdose of sublingual asenapine may be reduced by at least about 30% or atleast about 40% and/or the intensity of fatigue relative to anequivalent dose of sublingual asenapine may be reduced.

(v) alternatively, the at least one asenapine-related side effect may bedizziness, and the incidence of dizziness relative to an equivalent doseof sublingual asenapine may be reduced by at least about 30%, at leastabout 40%, at least about 70% or at least about 80%.

As concerns the type of side effects, it should be noted that fatigueand somnolence, while designating clinically different conditions, havecommon and/or similar symptoms and may be therefore difficult todistinguish, in particular if not followed on a long term.

In accordance with another specific aspect, the present invention isalso related to a method of treatment, and in particular a method oftreating a human patient.

The invention is in particular related to a method of treatingpsychosis, and in particular to a method of treating one or moreconditions selected from schizophrenia, bipolar disorder, posttraumaticstress disorder, major depressive disorder, dementia related psychosis,agitation and manic disorder, and preferably to a method of treatingschizophrenia and/or bipolar disorder in a human patient, and inparticular acute manic or mixed episodes of bipolar disorder includingapplying a transdermal therapeutic system according to the invention tothe skin of a human patient.

In certain embodiments, the invention is also related to a method oftreating acute manic or mixed episodes of bipolar disorder in an adultor a pediatric patient 10 to 17 years of age. In certain embodiments,the invention is also related to a method of treating bipolar disorderin a human patient, in particular an adult, as an adjunctive treatmentto lithium or valproate. In certain embodiments, the invention is alsorelated to a maintenance monotherapy treatment in a method of treatingbipolar disorder in a human patient, in particular an adult.

The invention is also related to a method of treatment by applying atransdermal therapeutic system according to the invention for at least24 hours or 1 day, at least 48 hours or 2 days, or at least 72 hours or3 days, and/or for up to 168 hours or 7 days, up to 120 hours or 5 days,or up to 96 hours or 4 days to the skin of a human patient. Thetransdermal therapeutic system according to the invention may inparticular be applied for 24 hours or 1 day, 48 hours or 2 days, or 84hours or 3.5 days to the skin of a human patient.

Accordingly the invention is also related to a method of treatment in anaround-the-clock treatment with a once-a-day TTS exchange mode (dosinginterval of 24 hours or 1 day), a twice-a-week TTS exchange mode (dosinginterval of 84 hours or 3.5 days) or a once-a-week TTS exchange mode(dosing interval of 168 hours, or 7 days).

In such a method, as previously outlined, the transdermal therapeuticsystem may provide a reduction in at least one asenapine-related sideeffect relative to an equivalent dose of sublingual asenapine.

In another embodiment, the present invention is also related to a methodof reducing, in a patient, at least one asenapine-related side effectrelative to an equivalent dose of sublingual asenapine, the methodcomprising administering a transdermal therapeutic system according tothe invention.

The invention is also related to a method of reducing at least oneasenapine-related side effect in a patient being treated with sublingualasenapine therapy, the method comprising

-   -   a) discontinuing sublingual asenapine therapy; and    -   b) administering a transdermal therapeutic system according to        the invention to the skin of the patient, wherein the        transdermal therapeutic system provides a reduction in at least        one asenapine-related side effect relative to an equivalent dose        of sublingual asenapine.

In such a method, the transdermal therapeutic system may deliver anamount of asenapine equivalent to the amount of asenapine originallyprovided by the sublingual asenapine therapy.

The relatively constant asenapine blood plasma concentration can bedescribed by several pharmacokinetic parameters as obtained in an invivo clinical study on human subjects.

Thus, in certain embodiments, the transdermal therapeutic system of thepresent invention:

-   -   provides by transdermal delivery a mean release rate of 0.5 to        20 mg/day, 0.5 to 20 mg/24 h, 500 to 20,000 μg/day, 500 to        20,000 μg/24 h, 0.021 to 0.833 mg/h or 21 to 833 μg/h,        preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h, 1,000 to 15,000        μg/day, 1,000 to 15,000 g/24 h, 0.042 to 0.625 mg/h or 42 to 625        μg/h, more preferably of 2.0 to 10 mg/day, 2.0 to 10 mg/24 h,        2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h, 0.083 to 0.417        mg/h or 83 to 417 μg/h over at least 48 hours or 2 days of        administration, or provides by transdermal delivery a mean        release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 72 hours or        3 days of administration, or provides by transdermal delivery a        mean release rate of 0.5 to 20 mg/day, 0.5 to 20 mg/24 h, 500 to        20,000 μg/day, 500 to 20,000 μg/24 h, 0.021 to 0.833 mg/h or 21        to 833 μg/h, preferably 1.0 to 15 mg/day, 1.0 to 15 mg/24 h,        1,000 to 15,000 μg/day, 1,000 to 15,000 μg/24 h, 0.042 to 0.625        mg/h or 42 to 625 μg/h, more preferably of 2.0 to 10 mg/day, 2.0        to 10 mg/24 h, 2,000 to 10,000 μg/day, 2,000 to 10,000 μg/24 h,        0.083 to 0.417 mg/h or 83 to 417 μg/h over at least 84 hours or        3.5 days of administration.

Further, in certain embodiments, the transdermal therapeutic system ofthe present invention:

-   -   provides by transdermal delivery an AUC₀₋₄₈ from 20 to 300        (ng/ml) h or from more than 300 to 450 (ng/ml) h and preferably        from 30 to 200 (ng/ml) h, or provides by transdermal delivery an        AUC₀₋₇₂ from 30 to 400 (ng/ml) h or from more than 400 to 600        (ng/ml) h and preferably from 50 to 300 (ng/ml) h, or provides        by transdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h or        from more than 450 to 700 (ng/ml) h and preferably from 60 to        350 (ng/ml) h.

Still further, in certain embodiments, the transdermal therapeuticsystem of the present invention:

-   -   provides by transdermal delivery a C_(max) to C₄₈ ratio of less        than 2.0, preferably of less than 1.5 and more preferably of        less than 1.3, or    -   provides by transdermal delivery a C_(max) to C₇₂ ratio of less        than 3.0, preferably of less than 2.5 and more preferably of        less than 2.0, or    -   provides by transdermal delivery a C_(max) to C84 ratio of less        than 3.5, preferably of less than 3.0, more preferably of less        than 2.5 and most preferably of less than 2.0.

Still further, in certain embodiments, the transdermal therapeuticsystem of the present invention:

provides by transdermal delivery a C_(max) value of from 0.5 to 10 ng/mland preferably of from 1 to 8 ng/ml.

In all such embodiments, as previously described, the TTS may be for usein a method of treating a human patient, wherein the transdermaltherapeutic system provides a reduction in at least oneasenapine-related side effect relative to an equivalent dose ofsublingual asenapine.

Process of Manufacture

The invention further relates to a process of manufacture of a matrixlayer for use in a transdermal therapeutic system and a correspondingmatrix layer structure and a corresponding TTS.

In accordance with the invention, the process of manufacture of a matrixlayer for use in a transdermal therapeutic system comprises the stepsof:

-   -   1) combining at least the components asenapine, acrylic polymer,        additional polymer, α-tocopherol and ascorbyl palmitate, in a        solvent to obtain a coating composition;    -   2) coating the coating composition onto a backing layer or a        release liner or any intermediate liner; and    -   3) drying the coated coating composition to form the matrix        layer.

In certain embodiments, in step 1), at least the components asenapine,acrylic polymer, additional polymer, α-tocopherol, ascorbyl palmitateand sodium metabisulfite are combined in a solvent to obtain the coatingcomposition.

In this process of manufacture, preferably in step 1) the asenapine isdissolved to obtain a coating composition.

In the above described process preferably the solvent is selected fromalcoholic solvents, in particular methanol, ethanol, isopropanol andmixtures thereof, and from non-alcoholic solvents, in particular ethylacetate, hexane, n-heptane, heptanes, petroleum ether, toluene, andmixtures thereof, and more preferably is selected from ethanol and ethylacetate.

In certain embodiments, the polymer in the above process is an acrylicpolymer and preferably a copolymer based on vinyl acetate,2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylateor a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate and2-hydroxyethyl-acrylate, which is provided as a solution and preferablyas a solution in ethyl acetate, n-heptane, heptanes, methanol, ethanolor any mixture thereof with a solids content of from 30 to 60% byweight.

In certain preferred embodiments, the polymer is an acrylic polymer andthe polymer is cross-linked. As outlined in detail above, commerciallyavailable acrylic polymers may be provided as a solution with or withouta cross-linking agent. In addition, an additional cross-linking agent(i.e. a cross-linking agent which does not come with the polymer) can beadded in step 1) of the process of manufacture.

Thus, in certain embodiments, an additional cross-linking agent is usedin step 1) to obtain the coating composition, wherein the cross-linkingagent preferably is an aluminium or a titanium cross-linking agent. Inalternative embodiments, no additional cross-linking agent is used instep 1) to obtain the coating composition.

If a polymer solution with cross-linking agent is used and/or if anadditional cross-linking agent is used in step 1), the polymer iscross-linked. In alternative embodiments, the polymer is an acrylicpolymer and the polymer is not cross-linked.

In step 3), drying is performed preferably in one or more cycles at roomtemperature and/or at a temperature of from 65 to 100° C., morepreferably from 70 to 90° C.

EXAMPLES

The present invention will now be more fully described with reference tothe accompanying examples. It should be understood, however, that thefollowing description is illustrative only and should not be taken inany way as a restriction of the invention. Numerical values provided inthe examples regarding the amount of ingredients in the composition orthe area weight may vary slightly due to manufacturing variability.

Reference Examples 1A-C Coating Composition

The formulations of the asenapine-containing coating compositions ofReference Examples la to lc are summarized in Table 1.1 below. Theformulations are based on weight percent, as also indicated in Table1.1.

TABLE 1.1 Ref. Ex. 1a Ref. Ex. 1b Ref. Ex. 1c Ingredient Amt Solids AmtSolids Amt Solids (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base1.00 9.9 15.0 10.0 15.0 10.0 Acrylic adhesive in ethyl acetate, 16.569.7 287.7 79.5 287.7 79.5 ethanol, heptanes and methanol, with atitanium cross-linking agent. Solids content of about 42.5% (Ref. Ex.1a) or 41.5% (Ref. Ex. 1b and 1c) by weight (Duro-Tak ™ 387-2516)Polyvinylpyrrolidone — — 15.0 10.0 15.0 10.0 (Povidone K90F)Polyvinylpyrrolidone 1.00 9.9 — — — — (Povidone K30) α-Tocopherol 0.050.50 0.76 0.50 0.76 0.50 Medium chain triglycerides 1.01 10.00 — — — —(Miglyol 812 N) Ethanol denat. (1% (v/v) 4.72 — 43.5 — 43.5 — methylethyl ketone) Total 24.3 100.0 361.9 100.0 361.9 100.0 Area weight[g/m²] 136.8 151.5 222.6 Asenapine content [mg/cm²] 1.357 1.514 2.224

Preparation of the Coating Composition

For Reference Example 1a, a stainless steel vessel was loaded with theα-tocopherol. The medium chain triglycerides, the acrylic pressuresensitive adhesive Duro-Tak™ 387-2516 and the polyvinylpyrrolidone wasadded and the mixture was then stirred until a clear solution wasobtained (about 40 min). The asenapine was added slowly and dissolvedunder stirring until a clear solution was obtained.

For Reference Examples 1b and 1c, a beaker was loaded with theα-tocopherol, the asenapine and the ethanol. The acrylic pressuresensitive adhesive Duro-Tak™ 387-2516 was added and the mixture was thenstirred until a clear solution was obtained (about 10 min). Thepolyvinylpyrrolidone was added slowly while stirring and dissolved understirring until a clear solution was obtained.

Coating of the Coating Composition of Reference Examples 1a and 1b

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (one side siliconized, 75 um thickness,which may function as release liner) and dried for approx. 10 min atroom temperature and 20 min. at 80° C. The coating thickness gave anarea weight of 136.8 g/m² (Ref. Ex. 1a) and 151.5 (Ref. Ex. 1b),respectively. The dried film was laminated with a polyethyleneterephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Coating of the Coating Composition, Reference Example 1c

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (siliconized, 100 μm thickness, whichmay function as release liner) and dried for approx. 10 min at roomtemperature and 20 min at 80° C. The coating thickness gave an areaweight of the matrix layer of 111.3 g/m². A first part of the dried filmwas laminated with a polyethylene terephthalate backing layer (23 μmthickness). The polyethylene terephthalate film (siliconized, 100 mmthickness, which may function as a release liner) of this first part wasthen removed and the adhesive site of the first part was laminated onthe adhesive site of a second, unmodified part of the dried film(comprising a release liner but not a backing layer). This results in anasenapine-containing self-adhesive layer structure with an area weightof the matrix layer of 222.6 g/m², with a backing layer and a releaseliner.

Preparation of the TTS (Concerning all Examples)

The individual systems (TTS) were then punched out from theasenapine-containing self-adhesive layer structure. In specificembodiments, a TTS as described above can be provided with a furtherself-adhesive layer of larger surface area, preferably with roundedcorners, comprising a pressure-sensitive adhesive matrix layer which isfree of active agent. This is of advantage when the TTS, on the basis ofits physical properties alone, does not adhere sufficiently to the skinand/or when the asenapine-containing matrix layer, for the purpose ofavoiding waste, has pronounced corners (square or rectangular shapes).The TTS are then punched out and sealed into pouches of the primarypackaging material as conventional in the art, i.e. under protectiveatmosphere, by flushing with nitrogen gas.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Example 1a as well as Reference Examples 1b and 1cwere determined by in vitro experiments in accordance with the OECDGuideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franzdiffusion cell. Split thickness human skin from cosmetic surgeries(female abdomen, date of birth 1955) was used. A dermatome was used toprepare skin to a thickness of 800 μm, with an intact epidermis for allTTS. Diecuts with an area of 1.151 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(phosphate buffer solution pH 5.5 with 0.1% saline azide asantibacteriological agent) at a temperature of 32±1° C. was measured andthe corresponding skin permeation rate calculated. The results are shownin Table 1.2 and FIG. 1 a.

TABLE 1.2 Skin permeation rate with SD [μg/(cm² h)] Elapsed Ref. Ex. 1a(n = 3) Ref. Ex. 1b (n = 2) Ref. Ex. 1c (n = 3) time [h] Rate SD Rate SDRate SD 2 0.00 0.00 0.00 0.00 0.00 0.00 4 0.23 0.03 0.20 0.20 0.27 0.078 1.40 0.17 1.41 0.58 1.25 0.13 12 4.03 0.50 4.24 1.18 3.44 0.08 16 6.620.70 6.79 1.58 5.95 0.14 20 8.42 0.79 8.73 1.53 8.02 0.14 24 9.72 0.679.74 1.51 9.45 0.15 32 8.96 0.71 9.29 0.90 9.15 0.21 40 10.15 0.53 11.120.37 10.84 0.30 48 10.07 0.35 10.50 0.11 11.10 1.07 56 9.51 0.25 10.120.05 10.49 0.35 64 9.14 0.17 9.88 0.04 10.27 0.41 72 8.76 0.38 9.47 0.2310.75 1.11 *: Standard on the deviation in this Example was, as in allother Examples, calculated based n-method.

Utilization of Asenapine

The utilization of asenapine at 72 hours was calculated based on thecumulative permeated amount at 72 hours and the initial asenapinecontent. The results are shown in Table 1.3 and in FIG. 1 b.

TABLE 1.3 Utilization of asenapine after 72 hours [%] Ref. Example 1aRef. Example 1b Ref. Example 1c (n = 3) (n = 2) (n = 3) 42.4 40.1 27.6

The in vitro experiments show the good skin permeation rate as well asthe utilization of asenapine of the previously developed referenceformulations (Ref Ex. 1b and 1c). Ref. Examples 1b and 1c correspond tothe formulation of Ref. Example 2d (except that the area weight ishigher), for which a successful in vivo clinical study has beenconducted (see below).

Examples 2A, 2B and Reference Examples 2C, 2D Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 2a and 2b as well as Reference Examples 2b and 2d aresummarized in Table 2.1 below. The formulations are based on weightpercent, as also indicated in Table 2.1.

TABLE 2.1 Ex. 2a Ex. 2b Ref. Ex. 2c Ref. Ex. 2d Ingredient Amt SolidsAmt Solids Amt Solids Amt Solids (Trade Name) [g] [%] [g] [%] [g] [%][g] [%] Asenapine base 30.0 10.0 1.00 10.0 54.0 6.0 135 10.0 Acrylicadhesive in ethyl 487.2 69.6 16.3 69.5 1820 83.5 2580 79.5 acetate,ethanol, heptanes and methanol, with a titanium cross-linking agent.Solids content of about 42.9% (Ex. 2a), 42.8% (Ex. 2b) or 41.5% (Ref.Ex. 2c and 2d) by weight (Duro-Tak ™ 387-2516) Polyvinylpyrrolidone 30.010.0 — — 90.0 10.0 135 10.0 (Povidone K90F) Polyvinylpyrrolidone — —1.00 10.0 — — — — (Povidone K30) α-Tocopherol 0.15 0.05 0.01 0.10 4.500.5 6.75 0.5 Ascorbyl palmitate 0.60 0.20 0.02 0.21 — — — — Sodiummetabisulfite 1.12 0.11 0.04 0.12 — — — — (30% aq. solution) Mediumchain 30.0 10.0 1.01 10.1 — — — — triglycerides (Miglyol 812 N) Ethanoldenat. (1% (v/v) 143.8 — 4.74 — 211.8 — 414.2 — methyl ethyl ketone)Total 722.9 100.0 24.1 100.0 2180.3 100.0 3271.0 100.0 Area weight[g/m²] 140.2-143.8 133.0 140* 140* Asenapine content 1.40-1.44 1.33 0.881.47 [mg/cm²] *Label area weight

Preparation of the Coating Composition

For Example 2a, a beaker was loaded with α-tocopherol. The ascorbylpalmitate, the medium chain triglycerides and the sodium metabisulfitesolution were added. The acrylic pressure sensitive adhesive Duro-Tak™387-2516 was added and the mixture was then stirred until a clearsolution was obtained. The polyvinylpyrrolidone was added slowly whilestirring and dissolved under stirring until a clear solution wasobtained. About 100 g of the ethanol were added and the resultingsolution was stirred. The asenapine was transferred to the beaker andthe mixture stirred. The remainder of the ethanol was added and thesolution stirred.

For Example 2b, a beaker was loaded with the asenapine. Theα-tocopherol, the ascorbyl palmitate, the medium chain triglycerides,the sodium metabisulfite solution, the acrylic pressure sensitiveadhesive Duro-Tak™ 387-2516, the polyvinylpyrrolidone and the ethanolwere added in this order to the asenapine. The resulting mixture wasstirred.

For Reference Examples 2c and 2d, a stainless steel vessel was loadedwith α-tocopherol. The acrylic pressure sensitive adhesive Duro-Tak™387-2516 was added and the mixture was then stirred until a clearsolution was obtained. The polyvinylpyrrolidone was added slowly whilestirring and dissolved under stirring until a clear solution wasobtained. The asenapine was suspended in the ethanol and transferred tothe stainless steel vessel. After addition of the asenapine, the mixturewas stirred until a clear, slightly yellow colored solution wasobtained.

Coating of the Coating Composition, Examples 2a and 2b

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of 133.0 for Example2b. For Example 2a, different films with an area weight of between 140.2and 143.8 g/m² were produced. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Coating of the Coating Composition of Reference Examples 2c and 2d

The resulting asenapine-containing coating composition was coated on apolyethylene terephthalate film (one side siliconized, 75 μm thickness,which may function as release liner) and dried for approx. 15 min at 80°C. The coating thickness gave an area weight of about 140 g/m² inaccordance with the label requirements (hereinafter, where reference ismade to a label value, it is understood that the actual value is withina tolerance of ±7.5% of the label value). The dried film was laminatedwith a polyethylene terephthalate backing layer (23 μm thickness) toprovide an asenapine-containing self-adhesive layer structure. Residualsolvents amounts fulfilled the requirement the ICH guideline Q3C (R3),i.e. methanol≤3,000 ppm, ethanol≤5,000 ppm, ethyl acetate≤5,000 ppm andn-heptane≤5,000 ppm.

Preparation of the TTS

See Example 1 for Examples 2a and 2b. For Reference Examples 2c and 2d,individual systems (TTS) of 10 cm² (Ref. Ex. 2c) as well as 15 cm² (Ref.Ex. 2d) were punched out from the asenapine-containing self-adhesivelayer structure.

Stability Measurements

A long term storage stability test was conducted for Examples 2a as wellas Reference

Examples 2c and 2d under different test conditions, i.e. storage at 25°C. and 60% relative humidity (RH), and at 40° C. and 75% RH. Allstability measurements disclosed herein (i.e. concerning all Examplesand Reference Examples) were conducted in accordance with the ICHstability guideline Q1A (R2). At different time points, samples weretaken from the TTS, extracted with an appropriate extraction solvent andthe amount of asenapine base, as well as various possible degradationsubstances was determined by a specific quantitative HPLC method with aUV photometric detector, based on the asenapine content calculated fromthe (actual) area weight of the tested TTS. The amount of other relatedsubstances is presented in accordance with the ICH stability guidelineQ1A (R2) throughout the whole description. The results are shown inTables 2.2 to 2.7. A plot of the sum of all related (i.e. possibledegradation product) substances is shown in FIGS. 2a and 2b .

TABLE 2.2 Detected amounts [%] Ex. 2a-25° C./60% 1 2 3 4 6 9 12 RHInitial month months months months months months months Asenapine base98 96 96 97 97 97 96 95 Asenapine N-Oxide <LOR <LOR <LOR <LOR n.d. <LOR<LOR 0.11 (Cis) Asenapine N-Oxide <LOR <LOR <LOR <LOR n.d. <LOR <LOR<LOR (Trans) Deschloro Asenapine n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d.Cis-Asenapine n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. TetradehydroAsenapine n.d. <LOR 0.14 n.d. 0.10 0.16 0.10 <LOR Other relatedsubstances n.d. n.d. n.d. n.d. n.d. n.d. 0.15 0.16 Sum of all related0.00 0.00 0.14 0.00 0.10 0.16 0.25 0.27 substances * n.d. = notdetected, LOR = Limit of Reporting (0.1%)

TABLE 2.3 Detected amounts [%] Ex. 2a-40° C./75% 1 2 3 4 5 6 RH Initialmonth months months months months months Asenapine base 98 95 95 95 9595 94 Asenapine N-Oxide <LOR <LOR <LOR <LOR 0.26 0.42 0.36 (Cis)Asenapine N-Oxide <LOR <LOR <LOR <LOR 0.24 0.37 0.32 (Trans) DeschloroAsenapine n.d. n.d. n.d. n.d. n.d. n.d. n.d. Cis-Asenapine n.d. <LOR<LOR n.d. n.d. n.d. n.d. Tetradehydro Asenapine n.d. 0.12 0.19 <LOR 0.210.26 0.26 Other related substances n.d. <LOR <LOR n.d. <LOR <LOR 0.12Sum of all related 0.00 0.12 0.19 0.00 0.71 1.05 1.06 substances * n.d.= not detected, LOR = Limit of Reporting (0.1%)

TABLE 2.4 Ref. Ex. 2c-25° C./ Detected amounts [%] 60% RH Initial† 1month† 3 months 9 months 12 months Asenapine base 92 92 94 88 88Asenapine 0.38 0.45 0.18 0.51 0.67 N-Oxide (Cis) Asenapine 0.40 0.480.19 0.49 0.62 N-Oxide (Trans) Deschloro n.d. n.d. n.d. n.d. n.d.Asenapine Cis-Asenapine n.d. n.d. n.d. n.d. n.d. Tetradehydro n.d. n.d.n.d. 0.10 0.30 Asenapine Other related n.d. n.d. 0.25 0.17 0.16substances** Sum of all 0.78 0.93 0.62 1.28 1.75 related substances*n.d. = not detected, LOR = Limit of Reporting (0.1%) †Due to asystematic error in the HPLC analysis (artefact peaks), the initial and1 month-values are too high and not reliable

TABLE 2.5 Detected amounts [%] Ref. Ex. 2c-40° C./75% RH Initial† 1month† 3 months 6 months Asenapine base 92 93 93 85 Asenapine N-Oxide(Cis) 0.38 0.52 0.46 0.93 Asenapine N-Oxide (Trans) 0.40 0.55 0.46 0.87Deschloro Asenapine n.d. n.d. n.d. n.d. Cis-Asenapine n.d. n.d. n.d.n.d. Tetradehydro Asenapine n.d. n.d. 0.10 0.23 Other relatedsubstances** n.d. n.d. 0.17 0.17 Sum of all related substances 0.78 1.071.19 2.21 *n.d. = not detected, LOR = Limit of Reporting (0.1%) †Due toa systematic error in the HPLC analysis (artefact peaks), the initialand 1 month-values are too high and not reliable

TABLE 2.6 Ref. Ex. Detected amounts [%] 2d-25° C./ 1 3 9 12 60% RHInitial† month† months months months Asenapine base 96 98 97 93 93Asenapine 0.36 0.41 0.22 0.37 0.59 N-Oxide (Cis) Asenapine 0.38 0.430.23 0.35 0.55 N-Oxide (Trans) Deschloro n.d. n.d. n.d. n.d. n.d.Asenapine Cis-Asenapine n.d. n.d. n.d. n.d. n.d. Tetradehydro n.d. n.d.<LOR <LOR 0.29 Asenapine Other related n.d. n.d. 0.21 0.14 0.13substances Sum of all 0.74 0.84 0.66 0.86 1.56 related substances *n.d.= not detected, LOR = Limit of Reporting (0.1%) †Due to a systematicerror in the HPLC analysis (artefact peaks), the initial and 1month-values are too high and not reliable

TABLE 2.7 Detected amounts [%] 1 3 6 Ref. Ex. 2d-40° C./75% RH Initial†month† months months Asenapine base 96 95 96 90 Asenapine N-Oxide (Cis)0.36 0.46 0.41 0.72 Asenapine N-Oxide (Trans) 0.38 0.48 0.40 0.67Deschloro Asenapine n.d. n.d. n.d. n.d. Cis-Asenapine n.d. n.d. n.d.n.d. Tetradehydro Asenapine n.d. n.d. 0.13 0.18 Other related substancesn.d. n.d. 0.14 n.d. Sum of all related substances 0.74 0.94 1.08 1.57*n.d. = not detected, LOR = Limit of Reporting (0.1%) †Due to asystematic error in the HPLC analysis (artefact peaks), the initial and1 month-values are too high and not reliable

The stability data show that, in certain embodiments of the invention,the initial stability as well as storage stability have beensubstantially improved when compared to the previously developedreference formulations (Ref. Ex. 2c and 2d), both in terms of the amountof asenapine base (in particular with respect to the amount of asenapinebase remaining after storage) as well as the sum of all related (i.e.possible degradation product) substances.

Examples 3A-E Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 3a-e are summarized in Table 3.1 below. The formulations arebased on weight percent, as also indicated in Table 3.1.

TABLE 3.1 Ex. 3a Ex. 3b Ex. 3c Ex. 3d Ex. 3e Amt Solids Amt Solids AmtSolids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g][%] [g] [%] [g] [%] Asenapine base 30.0 10.0 30.0 10.0 30.0 10.0 4.0010.0 4.00 10.0 Acrylic adhesive in ethyl 488.0 69.7 — — — — — — — —acetate, ethanol, heptanes and methanol, with a titanium cross-linkingagent. Solids content ~42.8% by wt. (Duro-Tak ™ 387-2516) Acrylicadhesive in ethyl — — 406.1 69.7 403.6 69.3 — — — — acetate. Solidscontent ~51.5% by wt. (Duro-Tak ™ 387-2287) Acrylic adhesive in ethyl —— — — — — 72.3 69.7 71.7 69.2 acetate. Solids content ~38.6 % by wt.(Duro-Tak ™ 387-4287) Aluminium acetylacetonate — — — — 1.38 0.46 — —0.18 0.46 Polyvinylpyrrolidone 30.0 10.0 30.0 10.0 30.0 10.0 4.00 10.04.00 10.0 (Povidone K30) α-Tocopherol 0.15 0.05 0.15 0.05 0.15 0.05 0.020.05 0.02 0.05 Ascorbyl palmitate 0.60 0.20 — — — — — — — — Ascorbylpalmitate (10.0% — — 6.16 0.21 6.01 0.21 0.80 0.20 0.80 0.20 in ethanol)Sodium metabisulfite (30% 0.56 0.056 0.59 0.06 0.56 0.06 0.08 0.06 0.080.06 aq. sol.) Medium chain triglycerides 30.1 10.0 30.0 10.0 30.0 10.04.01 10.0 4.01 10.0 (Miglyol 812 N) Ethanol denat. (1% (v/v) 143.2 —220.3 — 221.9 — 11.5 — 12.1 — methyl ethyl ketone) Total 722.6 100.0723.3 100.0 723.6 100.0 96.7 100.0 96.9 100.0 Area weight [g/m²]135.9-147.0 144.2-150.1 143.1-150.7 149.7 146.8 Asenapine content[mg/cm²] 1.36-1.47 1.44-1.50 1.43-1.51 1.50 1.47

Preparation of the Coating Composition

The coating composition of Example 3a was prepared as described inExample 2a.

For Examples 3b and 3c, a beaker was loaded with α-tocopherol. Themedium chain triglycerides, the sodium metabisulfite solution and theacrylic pressure sensitive adhesive Duro-Tak™ 387-2287 were added inthis order and the mixture was then stirred. The ascorbyl palmitatesolution was added dropwise under stirring, the polyvinylpyrrolidone wasadded thereafter while stirring, and, for Example 3c, the aluminiumacetylacetonate was added. The asenapine was transferred to the mixturewith the ethanol in several portions, and the resulting mixture wasstirred.

For Examples 3d and 3e, a beaker was loaded with α-tocopherol. Themedium chain triglycerides, the sodium metabisulfite solution, theacrylic pressure sensitive adhesive Duro-Tak™ 387-4287, the ascorbylpalmitate solution and the polyvinylpyrrolidone were added in this orderand the mixture was then stirred. The asenapine was added and themixture stirred. The ethanol was added while stirring (Ex. 3d) or thealuminium acetylacetonate was dissolved in the ethanol and added whilestirring (Ex. 3e).

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 149.7 g/m² (Example 3d) and 146.8 g/m² (Example 3e), respectively.For Examples 3a, 3b and 3c, different films with an area weight ofbetween 135.9 and 147.0 g/m², 144.2 and 150.1 g/m², and 143.1 and 150.7g/m² were produced, respectively. The dried film was laminated with apolyethylene terephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Stability Measurements

A long term storage stability test was conducted for Examples 3a to 3cunder different test conditions, i.e. storage at 25° C. and 60% relativehumidity (RH), and at 40° C. and 75% RH. At different time points,samples were taken from the TTS, extracted with an appropriateextraction solvent and the amount of asenapine base, as well as variouspossible degradation substances was determined by a specificquantitative HPLC method with a UV photometric detector, based on theasenapine content calculated from the (actual) area weight of the testedTTS. The results are shown in Tables 3.2 to 3.7. A plot of the sum ofall related (i.e. possible degradation product) substances is shown inFIGS. 3a and 3 b.

Further, in the same way, the amount of asenapine base, as well asvarious possible degradation substances was determined for TTS ofExamples 2a, 2b, 3d and 3e, stored at 5° C. (packaged under N2atmosphere as outlined above) for 4.5, 4, 2 and 2 months, respectively.The results are shown in Table 3.8 and in FIG. 3c .

TABLE 3.2 Detected amounts [%] Ex. 3a-25° C./60% RH Initial 1 month 2months 3 months Asenapine base 96 95 96 96 Asenapine N-Oxide (Cis) <LOR<LOR <LOR 0.16 Asenapine N-Oxide (Trans) 0.10 <LOR <LOR 0.15 DeschloroAsenapine n.d. n.d. n.d. n.d. Cis-Asenapine n.d. <LOR n.d. n.d.Tetradehydro Asenapine n.d. n.d. <LOR <LOR Other related substances n.d.n.d. n.d. n.d. Sum of all related substances 0.10 0.00 0.00 0.31 *n.d. =not detected, LOR = Limit of Reporting (0.1%)

TABLE 3.3 Detected amounts [%] Ex. 3a-40° C./75% RH Initial 1 month 2months 3 months Asenapine base 96 95 95 94 Asenapine N-Oxide (Cis) <LOR0.13 0.28 0.38 Asenapine N-Oxide (Trans) 0.10 0.13 0.25 0.33 DeschloroAsenapine n.d. n.d. n.d. n.d. Cis-Asenapine n.d. 0.11 n.d. n.d.Tetradehydro Asenapine n.d. <LOR 0.16 <LOR Other related substances n.d.<LOR <LOR n.d. Sum of all related substances 0.10 0.37 0.69 0.71 *n.d. =not detected, LOR = Limit of Reporting (0.1%)

TABLE 3.4 Detected amounts [%] Ex. 3b-25° C./60% RH Initial 1 month 2months Asenapine base 96 96 94 Asenapine N-Oxide (Cis) <LOR 0.17 0.22Asenapine N-Oxide (Trans) <LOR 0.17 0.22 Deschloro Asenapine n.d. n.d.n.d. Cis-Asenapine n.d. n.d. n.d. Tetradehydro Asenapine n.d. <LOR <LOROther related substances n.d. <LOR n.d. Sum of all related substances0.00 0.34 0.44 *n.d. = not detected, LOR = Limit of Reporting (0.1%)

TABLE 3.5 Detected amounts [%] Ex. 3b-40° C./75% RH Initial 1 month 2months Asenapine base 96 95 92 Asenapine N-Oxide (Cis) <LOR 0.41 0.90Asenapine N-Oxide (Trans) <LOR 0.40 0.91 Deschloro Asenapine n.d. n.d.n.d. Cis-Asenapine n.d. 0.15 n.d. Tetradehydro Asenapine n.d. 0.11 0.13Other related substances n.d. 0.21 0.15 Sum of all related substances0.00 1.28 2.09 *n.d. = not detected, LOR = Limit of Reporting (0.1%)

TABLE 3.6 Detected amounts [%] Ex. 3c-25° C./60% RH Initial 1 month 2months Asenapine base 96 99 96 Asenapine N-Oxide (Cis) <LOR 0.14 0.18Asenapine N-Oxide (Trans) <LOR 0.14 0.18 Deschloro Asenapine n.d. n.d.n.d. Cis-Asenapine n.d. <LOR n.d. Tetradehydro Asenapine n.d. <LOR <LOROther related substances n.d. <LOR n.d. Sum of all related substances0.00 0.28 0.36 *n.d. = not detected, LOR = Limit of Reporting (0.1%)

TABLE 3.7 Detected amounts [%] Ex. 3c-40° C./75% RH Initial 1 month 2months Asenapine base 96 95 93 Asenapine N-Oxide (Cis) <LOR 0.24 0.42Asenapine N-Oxide (Trans) <LOR 0.24 0.41 Deschloro Asenapine n.d. n.d.n.d. Cis-Asenapine n.d. n.d. n.d. Tetradehydro Asenapine n.d. 0.11 0.10Other related substances n.d. 0.14 <LOR Sum of all related substances0.00 0.73 0.93 *n.d. = not detected, LOR = Limit of Reporting (0.1%)

TABLE 3.8 Detected amounts [%] Ex. 2a Ex. 2b Ex. 3d Ex. 3e TTS stored at5° C. 4.5 months 4 months 2 months 2 months Asenapine base 96  97  96 96  Asenapine N-Oxide (Cis) < LOR < LOR 0.14 < LOR Asenapine N-Oxide(Trans) < LOR < LOR 0.14 < LOR Deschloro Asenapine n.d. n.d. n.d. n.d.Cis-Asenapine n.d. n.d. n.d. n.d. Tetradehydro Asenapine < LOR <LOQ <LOR < LOR Other related substances < LOR n.d. n.d. n.d. Sum of allrelated substances   0.00   0.00   0.28   0.00 * n.d. = not detected,LOR = Limit of Reporting (0.1%)

The stability data show that, in certain embodiments of the invention,the TTS provide excellent initial as well as storage stability.

Examples 4A and B Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 4a and 4b are summarized in Table 4.1 below. The formulationsare based on weight percent, as also indicated in Table 4.1.

TABLE 4.1 Ex. 4a Ex. 4b Amt Solids Amt Solids Ingredient (Trade Name)[g] [%] [g] [%] Asenapine base 1.00 10.0 1.00 10.0 Acrylic adhesive inethyl acetate, 16.3 69.7 — — ethanol, heptanes and methanol, with atitanium cross-linking agent. Solids content ~42.9% by wt. (Duro-Tak ™387-2516) Acrylic adhesive in ethyl acetate. — — 13.4 68.9 Solidscontent ~51.8% by weight (Duro-Tak ™ 387-2287) Aluminium acetylacetonate— — 0.05 0.53 Polyvinylpyrrolidone (Povidone 1.00 10.0 1.01 10.1 K90F)α-Tocopherol 0.005 0.05 0.008 0.08 Ascorbyl palmitate 0.02 0.20 0.020.21 Sodium metabisulfite (30% aq. sol.) 0.02 0.07 0.02 0.07 Mediumchain triglycerides 1.00 10.0 1.02 10.1 (Miglyo1 812 N) Ethanol denat.(1% (v/v) methyl 4.79 — 7.73 — ethyl ketone) Total 24.1 100.0 24.3 100.0Area weight [g/m²] 143.2  144.2  Asenapine content [mg/cm²]  1.43  1.44

Preparation of the Coating Composition

The coating composition of Example 4a was prepared as described inExample 2b.

For Example 4b, a beaker was loaded with the asenapine. Theα-tocopherol, the ascorbyl palmitate, the medium chain triglycerides,the sodium metabisulfite solution, the acrylic pressure sensitiveadhesive Duro-Tak™ 387-2287 and the polyvinylpyrrolidone were added inthis order to the asenapine and the resulting mixture was stirred. Thealuminium acetylacetonate was dissolved in the ethanol and added to themixture while stirring.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 143.2 g/m² (Example 4a) and 144.2 g/m² (Example 4b), respectively.The dried film was laminated with a polyethylene terephthalate backinglayer (23 μm thickness) to provide an asenapine-containing self-adhesivelayer structure.

Preparation of the TTS

See Example 1.

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Examples 4a and 4b as well as Reference Example 1cwere determined by in vitro experiments in accordance with the OECDGuideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franzdiffusion cell. Split thickness human skin from cosmetic surgeries(female abdomen, date of birth 1982) was used. A dermatome was used toprepare skin to a thickness of 800 gm, with an intact epidermis for allTTS. Diecuts with an area of 1.188 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(phosphate buffer solution pH 5.5 with 0.1% saline azide asantibacteriological agent) at a temperature of 32±1° C. was measured andthe corresponding skin permeation rate calculated. The results are shownin Table 4.2 and FIG. 4a .

TABLE 4.2 Skin permeation rate with SD [μg/(cm² h)] Elapsed Ref. Ex.1c(n = 3) Ex. 4a(n = 3) Ex. 4b(n = 3) time [h] Rate SD Rate SD Rate SD 40.30 0.20 0.16 0.01 0.18 0.06 8 2.39 0.74 2.31 0.22 2.59 0.75 12 6.051.53 6.52 0.46 7.09 1.78 24 10.47 1.84 10.64 0.52 10.15 1.63 48 12.301.31 11.57 0.31 11.69 1.25 72 12.03 0.90 10.26 0.13 10.51 0.12 *:Standard on the deviation in this Example was, as in all other Examples,calculated based n-method.

Utilization of Asenapine

The utilization of asenapine at 72 hours was calculated based on thecumulative permeated amount at 72 hours and the initial asenapinecontent. The results are shown in Table 4.3 and in FIG. 4b .

TABLE 4.3 Utilization of asenapine after 72 hours [%] Ref. Example 1cExample 4a Example 4b (n = 3) (n = 3) (n = 3) 33.5 47.9 44.7

The in vitro experiments show that the good skin permeation rate as wellas the utilization of asenapine of the previously developed referenceformulation (Ref. Ex. 1c) could be surprisingly maintained forformulations in accordance with certain embodiments of the presentinvention, comprising a considerable amount of medium chaintriglycerides as tackifier as well as a specific combination ofstabilizers. Reference Example 1c corresponds to the formulation ofReference Example 2d (except that the area weight is higher), for whicha successful in vivo clinical study has been conducted (see below).

Reference Examples 5A-C Coating Composition

The formulations of the asenapine-containing coating compositions ofReference Examples 5a, 5b and 5c are summarized in Table 5.1 below. Theformulations are based on weight percent, as also indicated in Table5.1.

TABLE 5.1 Ref. Ex. 5a Ref. Ex. 5b Ref. Ex. 5c Ingredient Amt Solids AmtSolids Amt Solids (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base1.80 5.96 1.80 6.00 1.80 6.00 Acrylic adhesive in ethyl 61.6 84.1 61.083.9 60.8 83.8 acetate, ethanol, heptanes and methanol, with a titaniumcross-linking agent. Solids content of about 41.3% by weight (Duro-Tak ™387-2516) Polyvinylpyrrolidone 3.00 9.93 3.00 10.0 3.00 10.0 (PovidoneK90F) Ascorbyl palmitate 0.003 0.01 0.03 0.10 0.06 0.20 Ethanol denat.(1% (v/v) 6.49 — 6.48 — 6.46 — methyl ethyl ketone) Total 72.9 100.0072.3 100.00 72.1 100.00 Area weight [g/m²] 150.9 146.7 146.2 Asenapinecontent [mg/cm²] 0.90 0.88 0.88

Preparation of the Coating Composition

A beaker was loaded with the ascorbyl palmitate. The acrylic pressuresensitive adhesive Duro-Tak™ 387-2516 was added, the mixture was stirredand the polyvinylpyrrolidone was added while stirring. The asenapine andthe ethanol were added consecutively and the mixture was stirred until aclear solution was obtained.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 150.9 g/m² (Reference Example 5a), 146.7 g/m² (Reference Example 5b)and 146.2 g/m² (Reference Example 5c), respectively. The dried film waslaminated with a polyethylene terephthalate backing layer (23 μmthickness) to provide an asenapine-containing self-adhesive layerstructure.

Preparation of the TTS

See Example 1.

Stability Measurements

The stability of the TTS of Reference Examples 5a to 5c, stored at 40°C. and 75% RH for 2.5 months, as well as of the TTS of ReferenceExamples 5a and 5c, stored at 25° C. and 60% RH for 12 months wasinvestigated. Samples were taken from the TTS, extracted with anappropriate extraction solvent and the amount of asenapine base, as wellas various possible degradation substances was determined by a specificquantitative HPLC method with a UV photometric detector, based on theasenapine content calculated from the (actual) area weight of the testedTTS. The results are shown in Tables 5.2 and 5.3 as well as FIGS. 5a and5b .

TABLE 5.2 TTS stored at 40° C./ Detected amounts [%] 75% RH For 2.5months Ref. Ex. 5a Ref Ex. 5b Ref. Ex. 5c Asenapine base 96 97 97Asenapine N-Oxide (Cis) 1.08 0.80 0.80 Asenapine N-Oxide (Trans) 1.040.76 0.74 Cis-Asenapine < LOR < LOR 0.15 Tetradehydro Asenapine 1.621.27 0.94 Other related substances 0.19 0.11 0.10 Sum of all relatedsubstances 3.93 2.94 2.73 * LOR = Limit of Reporting (0.1%)

TABLE 5.3 TTS stored at 25° C./ Detected amounts [%] 60% RH For 12months Ref. Ex. 5a Ref Ex. 5c Asenapine N-Oxide (Cis) 1.24 1.15Asenapine N-Oxide (Trans) 1.18 1.06 Tetradehydro Asenapine 0.25 0.24Other related substances 0.11 < LOR Sum of all related substances 2.782.45 * LOR = Limit of Reporting (0.1%)

The stability data of Reference Examples 5a-c show that the presence andcertain higher amounts of ascorbyl palmitate have a positive influenceon initial as well as storage stability of asenapine formulationscomprising a matrix layer based on an acrylic adhesive and including anadditional polymer (polyvinylpyrrolidone).

Reference Examples 6A-D Coating Composition

The formulations of the asenapine-containing coating compositions ofReference Examples 6a, 6b, 6c and 6d are summarized in Table 6.1 below.The formulations are based on weight percent, as also indicated in Table6.1.

TABLE 6.1 Ref. Ex. 6a Ref. Ex. 6b Ref. Ex. 6c Ref. Ex. 6d Ingredient AmtSolids Amt Solids Amt Solids Amt Solids (Trade Name) [g] [%] [g] [%] [g][%] [g] [%] Asenapine base 1.80 5.99 1.80 6.00 1.80 5.95 1.80 6.00Acrylic adhesive in ethyl 61.1 84.0 61.1 84.0 61.6 84.1 60.7 83.5acetate, ethanol, heptanes and methanol, with a titanium cross-linkingagent. Solids content of about 41.3% by weight (Duro-Tak ™ 387-2516)α-Tocopherol — — 0.002 0.006 0.02 0.05 0.15 0.5 Polyvinylpyrrolidone3.00 10.0 3.00 10.0 3.00 9.92 3.00 10.0 (Povidone K90F) Ethanol denat.(1% (v/v) 6.47 — 6.48 — 6.47 — 6.47 — methyl ethyl ketone) Total 72.4100.0 72.4 100.0 72.9 100.0 72.1 100.0 Area weight [g/m²] 144.2 133.0149.0 147.2 Asenapine content 0.86 0.80 0.89 0.88 [mg/cm²]

Preparation of the Coating Composition

For Reference Example 6a, a beaker was loaded with the acrylic pressuresensitive adhesive Duro-Tak™ 387-2516. The polyvinylpyrrolidone wasadded while stirring. The asenapine and the ethanol were addedconsecutively and the mixture was stirred.

For Reference Examples 6b to 6d, a beaker was loaded with theα-Tocopherol. The acrylic pressure sensitive adhesive Duro-Tak™ 387-2516was added, the mixture was stirred and the polyvinylpyrrolidone wasadded while stirring. The asenapine and the ethanol were addedconsecutively and the mixture was stirred until a clear solution wasobtained.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 144.2 g/m² (Reference Example 6a), 133.0 g/m² (Reference Example 6b),149.0 g/m² (Reference Example 6c) and 147.2 g/m² (Reference Example 6d),respectively. The dried film was laminated with a polyethyleneterephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Stability Measurements

The stability of the TTS of Reference Examples 6a to 6d, stored at 40°C. and 75% RH for 2.5 months, as well as of the TTS of ReferenceExamples 6a, 6c and 6d, stored at 25° C. and 60% RH for 12 months wasinvestigated. Samples were taken from the TTS, extracted with anappropriate extraction solvent and the amount of asenapine base, as wellas various possible degradation substances was determined by a specificquantitative HPLC method with a UV photometric detector, based on theasenapine content calculated from the (actual) area weight of the testedTTS. The results are shown in Tables 6.2 and 6.3 as well as FIGS. 6a and6b .

TABLE 6.2 Detected amounts [%] TTS stored at 40° C./ Ref. Ex. Ref. Ex.Ref. Ex. Ref. Ex. 75% RH For 2.5 months 6a 6b 6c 6d Asenapine base 97 9897 98 Asenapine N-Oxide (Cis) 0.82 0.59 0.61 0.56 Asenapine N-Oxide(Trans) 0.84 0.61 0.59 0.54 Cis-Asenapine n.d. < LOR < LOR n.d.Tetradehydro Asenapine 1.63 0.93 1.04 1.14 Other related substances 0.180.25 0.25 0.24 Sum of all related 3.47 2.38 2.49 2.48 substances *LOR =Limit of Reporting (0.1%)

TABLE 6.3 TTS stored at 25° C./ Detected amounts [%] 60% RH For 12months Ref Ex. 6a Ref Ex. 6c Ref Ex. 6d Asenapine N-Oxide (Cis) 0.950.77 0.64 Asenapine N-Oxide (Trans) 0.91 0.72 0.60 TetradehydroAsenapine 0.20 0.18 0.16 Other related substances 0.11 0.15 0.15 Sum ofall related substances 2.17 1.82 1.55

The stability data of Reference Examples 6a-d show that the presence andcertain higher amounts of α-Tocopherol have a positive influence oninitial as well as storage stability of asenapine formulationscomprising a matrix layer based on an acrylic adhesive and including anadditional polymer (polyvinylpyrrolidone).

Reference Examples 7A-D Coating Composition

The formulations of the asenapine-containing coating compositions ofReference Examples 7a, 7b, 7c and 7d are summarized in Table 7.1 below.The formulations are based on weight percent, as also indicated in Table7.1.

TABLE 7.1 Ref. Ex. 7a Ref. Ex. 7b Ref. Ex.7c Ref. Ex. 7d Ingredient AmtSolids Amt Solids Amt Solids Amt Solids (Trade Name) [g] [%] [g] [%] [g][%] [g] [%] Asenapine base 1.80 5.89 1.80 5.99 1.80 6.00 1.80 5.97Acrylic adhesive 62.4 84.3 61.1 84.0 60.9 84.0 61.4 84.0 in ethylacetate, ethanol, heptanes and methanol, with a titanium cross-linkingagent. Solids content of about 41.3% by weight (Duro-Tak ™ 387-2516)Sodium metabisulfite (30% — — 0.009 0.01 0.03 0.03 0.06 0.06 aq. sol.)Polyvinylpyrrolidone 3.00 9.81 3.00 9.99 3.00 10.0 3.00 9.94 (PovidoneK90F) Ethanol denat. (1% (v/v) 6.48 — 6.48 — 6.47 — 6.47 — methyl ethylketone) Purified water 0.02 — — — — — — — Total 73.7 100.0 72.4 100.072.2 100.0 72.7 100.0 Area weight [g/m²] 147.7 148.3 147.6 146.7Asenapine content 0.87 0.89 0.89 0.88 [mg/cm²]

Preparation of the Coating Composition

For Reference Example 7a, a beaker was loaded with the purified waterand the acrylic pressure sensitive adhesive Duro-Tak™ 387-2516 wasadded. To this mixture, the polyvinylpyrrolidone was added whilestirring. The asenapine and the ethanol were added consecutively and themixture was stirred.

For Reference Examples 7b to 7d, a beaker was loaded with the sodiummetabisulfite solution and the acrylic pressure sensitive adhesiveDuro-Tak™ 387-2516 was added. The polyvinylpyrrolidone was added whilestirring. The asenapine and the ethanol were added consecutively and themixture was stirred until a clear solution was obtained.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 147.7 g/m² (Reference Example 7a), 148.3 g/m² (Reference Example 7b),147.6 g/m² (Reference Example 7c) and 146.7 g/m² (Reference Example 7d),respectively. The dried film was laminated with a polyethyleneterephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Stability Measurements

The stability of the TTS of Reference Examples 7a to 7d, stored at 40°C. and 75% RH for 2.5 months was investigated. Samples were taken fromthe TTS, extracted with an appropriate extraction solvent and the amountof asenapine base, as well as various possible degradation substanceswas determined by a specific quantitative HPLC method with a UVphotometric detector, based on the asenapine content calculated from the(actual) area weight of the tested TTS. The results are shown in Table7.2 and in FIG. 7 a.

Further, the amount of asenapine base, as well as various possibledegradation substances of the coating compositions of Reference Examples6a as well as 7a to 7d was determined also by a specific quantitativeHPLC method with a UV photometric detector few days after preparation ofthe coating compositions. The results are shown in Table 7.3 and in FIG.7b .

TABLE 7.2 Detected amounts [%] TTS stored at 40° C./ Ref Ex. Ref Ex. RefEx. Ref Ex. 75% RH For 2.5 months 7a 7b 7c 7d Asenapine base 96 96 96 93Asenapine N-Oxide (Cis) 0.88 0.94 0.87 1.51 Asenapine N-Oxide (Trans)0.91 0.97 0.89 1.51 Tetradehydro Asenapine 1.71 2.00 2.46 3.76 Otherrelated substances 0.21 0.18 0.12 < LOR Sum of all related 3.71 4.094.34 6.78 substances * LOR = Limit of Reporting (0.1%)

TABLE 7.3 Coating compositions Detected amounts [%] (prior to Ref. Ex.Ref. Ex. Ref. Ex. Ref. Ex. Ref. Ex. coating) 6a 7a 7b 7c 7d Asenapine100 100 99 100 100 base Asenapine 0.12 0.12 0.21 < LOR n.a. N-Oxide(Cis) Asenapine 0.14 0.14 0.23 0.10 n.a. N-Oxide (Trans) Deschloro < LOR< LOR < LOR < LOR < LOR Asenapine Tetradehydro n.a. n.a. n.a. < LOR 0.11Asenapine Sum of all 0.26 0.26 0.44 0.10 0.11 related substances * LOR =Limit of Reporting (0.1%)

The stability data of Reference Examples 7a-d show that the presence andcertain higher amounts of sodium metabisulfite have a positive influenceon initial stability of asenapine formulations comprising a matrix layerbased on an acrylic adhesive and including an additional polymer(polyvinylpyrrolidone).

Examples 8A-E

Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 8a to 8e are summarized in Table 8.1 below. The formulationsare based on weight percent, as also indicated in Table 8.1.

TABLE 8.1 Ref. Ex. 8a Ref. Ex. 8b Ref. Ex. 8c Ref. Ex. 8d Ref. Ex. 8eIngredient (Trade Amt Solids Amt Solids Amt Solids Amt Solids Amt SolidsName) [g] [%] [g] [%] [g] [%] [g] [%] [g] [%] Asenapine base 1.80 6.001.80 5.99 1.80 5.99 1.80 6.00 1.80 6.00 Acrylic adhesive in 60.6 83.461.1 83.9 61.0 83.8 60.8 83.7 60.8 83.8 ethyl acetate, ethanol, heptanesand methanol, with a titanium cross-linking agent. Solids content ~41.3%by wt. (Duro-Tak ™ 387- 2516) Polyvinylpyrrolidone 3.00 10.0 3.00 9.993.00 9.98 3.00 10.0 3.00 10.0 (Povidone K90F) α-Tocopherol 0.15 0.500.02 0.06 0.03 0.10 0.03 0.10 0.02 0.05 Ascorbyl palmitate 0.03 0.100.02 0.06 0.03 0.10 0.06 0.20 0.06 0.20 Ethanol denat. (1% 6.50 — 6.71 —6.50 — 6.51 — 6.49 — (v/v) methyl ethyl ketone) Total 72.1 100.0 72.7100.0 72.4 100.0 72.2 100.0 72.2 100.0 Area weight [g/m²] 144.7 139.2147.5 145.8 144.8 Asenapine content 0.87 0.83 0.88 0.88 0.87 [mg/cm²]

Preparation of the Coating Composition

For Examples 8a to 8e, a beaker was loaded with the α-Tocopherol and theascorbyl palmitate, the acrylic pressure sensitive adhesive Duro-Tak™387-2516 was added and the resulting mixture stirred. Thepolyvinylpyrrolidone was added while stirring. The asenapine and theethanol were added consecutively and the mixture was stirred until aclear solution was obtained.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 144.7 g/m² (Example 8a), 139.2 g/m² (Example 8b), 147.5 g/m² (Example8c), 145.8 g/m² (Example 8d) and 144.8 g/m² (Example 8e), respectively.The dried film was laminated with a polyethylene terephthalate backinglayer (23 μm thickness) to provide an asenapine-containing self-adhesivelayer structure.

Preparation of the TTS

See Example 1.

Stability Measurements

The stability of the TTS of Examples 8a to 8e, stored at 40° C. and 75%RH for 2.5 months, as well as at 25° C. and 60% RH for 12 months wasinvestigated. Samples were taken from the TTS, extracted with anappropriate extraction solvent and the amount of asenapine base, as wellas various possible degradation substances was determined by a specificquantitative HPLC method with a UV photometric detector, based on theasenapine content calculated from the (actual) area weight of the testedTTS. The results are shown in Tables 8.2 and 8.3 as well as FIGS. 8a and8b .

TABLE 8.2 TTS stored at 40° C./ Detected amounts [%] 75% RH For 2.5months Ex. 8a Ex. 8b Ex. 8c Ex. 8d Ex. 8e Asenapine base 98 97 98 99 99Asenapine N-Oxide (Cis) 0.44 0.60 0.39 0.29 0.23 Asenapine N-Oxide(Trans) 0.43 0.60 0.39 0.28 0.23 Cis-Asenapine 0.14 0.15 0.10 0.10 < LORTetradehydro Asenapine 0.74 1.01 0.70 0.37 0.33 Other related substances0.20 0.21 0.16 0.14 0.13 Sum of all related 1.95 2.57 1.74 1.18 0.92substances * LOR = Limit of Reporting (0.1%)

TABLE 8.3 TTS stored at 25° C./ Detected amounts [%] 60% RH For 12months Ex. 8a Ex. 8b Ex. 8c Ex. 8d Ex. 8e Asenapine N-Oxide (Cis) 0.700.92 0.61 0.47 0.44 Asenapine N-Oxide (Trans) 0.65 0.85 0.57 0.43 0.42Tetradehydro Asenapine 0.20 0.25 0.20 0.14 0.17 Other related substances0.10 0.11 0.10 < LOR 0.13 Sum of all related substances 1.65 2.13 1.481.04 1.16 * LOR = Limit of Reporting (0.1%)

The stability data of Examples 8a-e show that positive influence ofα-Tocopherol and ascorbyl palmitate on initial as well as storagestability of asenapine formulations comprising a matrix layer based onan acrylic adhesive and including an additional polymer(polyvinylpyrrolidone) is synergistic for certain amounts ofα-Tocopherol and ascorbyl palmitate.

Examples 9A-E Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 9a to 9e are summarized in Table 9.1 below. The formulationsare based on weight percent, as also indicated in Table 9.1.

TABLE 9.1 Ex. 9a Ex. 9b Ex. 9c Ex. 9d Ex. 9e Ingredient (Trade AmtSolids Amt Solids Amt Solids Amt Solids Amt Solids Name) [g] [%] [g] [%][g] [%] [g] [%] [g] [%] Asenapine base 40.0 10.0 40.0 10.0 40.0 10.08.00 10.0 8.00 10.0 Acrylic adhesive in 676.4 69.7 674.2 69.4 672.4 69.2134.2 68.9 133.3 68.6 ethyl acetate, ethanol, heptanes and methanol,with a titanium cross- linking agent. Solids content ~41.2% by wt.(Duro-Tak ™ 387-2516) Polyvinylpyrrolidone 40.0 10.0 40.0 10.0 39.9 10.08.00 10.0 8.00 10.0 (Povidone K30) α-Tocopherol 0.21 0.05 0.20 0.05 0.210.05 0.13 0.17 0.06 0.07 Ascorbyl palmitate 8.07 0.20 16.5 0.41 24.10.60 4.82 0.6 1.62 0.2 (10% sol. in ethanol denat, containing 1 % (v/v)methyl ethyl ketone) Sodium metabisulfite 1.51 0.11 1.51 0.11 1.51 0.110.29 0.11 0.33 0.12 (30 % aq. sol.) Medium chain 40.0 10.0 40.0 10.040.1 10.0 8.23 10.3 8.00 10.0 triglycerides (Miglyol 812 N) Isononanoicacid — — — — — — — — 0.80 1.00 (3,5,5- Trimethylhexanoic acid, 97%)Ethanol denat. (1 % 175.9 — 175.0 — 191.4 — 29.0 — 32.7 — (v/v) methylethyl ketone) Total 982.1 100.0 987.4 100.0 1009.6 100.0 192.7 100.0192.8 100.0 Area weight [g/m²] 140.2-148.7 140.5-145.6 137.0-148.9 136.6135.1 Asenapine content 1.402-1.487 1.405-1.456 1.370-1.489 1.366 1.351[mg/cm²]

Preparation of the Coating Composition

A stainless steel vessel (Examples 9a to 9c) or a beaker (Examples 9dand 9e) was loaded with a part of the ethanol, the sodium metabisulfitesolution was added dropwise under stirring and the mixture stirred atleast 10 min. The α-Tocopherol and the ascorbyl palmitate solution wereadded dropwise under stirring and the resulting mixture stirred for atleast 20 min.

After adding the medium chain triglycerides under stirring,polyvinylpyrrolidone was weighed in a beaker and added to the mixtureunder stirring. In case of Example 9e, the isononanoic acid was addedand the mixture stirred for at least 10 min. before adding thepolyvinylpyrrolidone. The acrylic pressure sensitive adhesive Duro-Tak™387-2516 was weighed into the reaction mixture, the resulting mixturewas stirred and allowed to stand, after which the asenapine was weighedin a beaker and added to the mixture with the remaining part of theethanol. The mixture was stirred until a clear solution was obtained.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 136.6 g/m² (Example 9d) and 135.1 g/m² (Example 9e), respectively.For Example 9a, different films with an area weight of between 140.2 and148.7 g/m² were produced. For Example 9b, different films with an areaweight of between 140.5 and 145.6 g/m² were produced. For Example 9c,different films with an area weight of between 137.0 and 148.9 g/m² wereproduced. The dried film was laminated with a polyethylene terephthalatebacking layer (23 μm thickness) to provide an asenapine-containingself-adhesive layer structure.

Preparation of the TTS

See Example 1.

Stability Measurements

A long term storage stability test was conducted for Examples 9a to 9eunder different test conditions, i.e. storage at 25° C. and 60% relativehumidity (RH), at 30° C. and 75% RH, and at 40° C. and 75% RH. Atdifferent time points, samples were taken from the TTS, extracted withan appropriate extraction solvent and the amount of asenapine base, aswell as various possible degradation substances was determined by aspecific quantitative HPLC method with a UV photometric detector, basedon the asenapine content calculated from the (actual) area weight of thetested TTS. The results are shown in Tables 9.2 to 9.16. A plot of thesum of all related (i.e. possible degradation product) substances isshown in FIGS. 9a to 9f , in comparison to Reference Example 2d (forstorage at 25° C. and 60% RH as well as at 40° C. and 75% RH).

TABLE 9.2 Detected amounts [%] Ex. 9a - 25° C./60% RH Initial 2 months 3months 6 months 9 months 12 months Asenapine base 96 96 95 95 95 95Asenapine N-Oxide (Cis) n.d. n.d. n.d. <LOR <LOR 0.11 Asenapine N-Oxide(Trans) n.d. n.d. n.d. <LOR <LOR 0.13 Tetradehydro Asenapine n.d. <LOR<LOR <LOR <LOR <LOR Other related substances n.d. n.d. n.d. <LOR n.d.<LOR Sum of all related substances 0.00 0.00 0.00 0.00 0.00 0.24 * n.d.= not detected, LOR = Limit of reporting (0.1%)

TABLE 9.3 Detected amounts [%] Ex. 9a - 30° C./75% RH Initial 2 months 3months 6 months 9 months 12 months Asenapine base 96 96 95 96 95 95Asenapine N-Oxide (Cis) n.d. n.d. n.d. 0.11 n.d. 0.13 Asenapine N-Oxide(Trans) n.d. n.d. n.d. 0.11 n.d. 0.14 Tetradehydro Asenapine n.d. <LOR<LOR <LOR <LOR <LOR Other related substances n.d. n.d. n.d. <LOR n.d.<LOR Sum of all related substances 0.00 0.00 0.00 0.22 0.00 0.27 * n.d.= not detected, LOR = Limit of reporting (0.1%)

TABLE 9.4 Detected amounts [%] Ex. 9a - 40° C./75% RH Initial 1 month 2months 3 months 6 months Asenapine base 96 96 96 94 95 Asenapine N-Oxide(Cis) n.d. n.d. n.d. <LOR 0.17 Asenapine N-Oxide (Trans) n.d. n.d. n.d.n.d. 0.16 Tetradehydro Asenapine n.d. <LOR 0.10 <LOR <LOR Other relatedsubstances n.d. n.d. <LOR n.d. 0.13 Sum of all related substances 0.000.00 0.10 0.00 0.46 * n.d. = not detected, LOR = Limit of reporting(0.1%)

TABLE 9.5 Detected amounts [%] Ex. 9b - 25° C./60% RH Initial 2 months 3months 6 months 9 months 12 months Asenapine base 96 96 95 95 95 95Asenapine N-Oxide (Cis) n.d. n.d. n.d. <LOR n.d. <LOR Asenapine N-Oxide(Trans) n.d. n.d. n.d. <LOR n.d. 0.10 Tetradehydro Asenapine n.d. <LOR<LOR <LOR <LOR <LOR Other related substances n.d. n.d. n.d. <LOR n.d.<LOR Sum of all related substances 0.00 0.00 0.00 0.00 0.00 0.10 * n.d.= not detected, LOR = Limit of reporting (0.1%)

TABLE 9.6 Detected amounts [%] Ex. 9b - 30° C./75% RH Initial 2 months 3months 6 months 9 months 12 months Asenapine base 96 95 95 95 94 94Asenapine N-Oxide (Cis) n.d. n.d. n.d. <LOR 0.12 0.20 Asenapine N-Oxide(Trans) n.d. n.d. n.d. <LOR 0.11 0.20 Tetradehydro Asenapine n.d. <LOR<LOR <LOR <LOR 0.13 Other related substances n.d. n.d. n.d. <LOR n.d.0.10 Sum of all related substances 0.00 0.00 0.00 0.00 0.23 0.63 * n.d.= not detected, LOR = Limit of reporting (0.1%)

TABLE 9.7 Detected amounts [%] 1 2 3 6 Ex. 9b - 40° C./75% RH Initialmonth months months months Asenapine base 96  97  96  94  95  AsenapineN-Oxide (Cis) n.d. n.d. n.d. n.d. < LOR Asenapine N-Oxide (Trans) n.d.n.d. n.d. n.d. < LOR Tetradehydro Asenapine n.d. < LOR   0.11 < LOR <LOR Other related substances n.d. n.d. n.d. n.d.   0.10 Sum of allrelated   0.00   0.00   0.11   0.00   0.10 substances * n.d. = notdetected, LOR = Limit of reporting (0.1%)

TABLE 9.8 Detected amounts [%] Ex. 9c - 25° C./60% RH Initial 2 months 3months 6 months 9 months 12 months Asenapine base 96 97 94 95 94 94Asenapine N-Oxide (Cis) n.d. n.d. <LOR <LOR 0.13 <LOR Asenapine N-Oxide(Trans) n.d. n.d. <LOR <LOR 0.13 <LOR Tetradehydro Asenapine <LOR <LOR<LOR <LOR <LOR <LOR Other related substances n.d. n.d. <LOR <LOR n.d.<LOR Sum of all related substances 0.00 0.00 0.00 0.00 0.26 0.00 * n.d.= not detected, LOR = Limit of reporting (0.1%)

TABLE 9.9 Detected amounts [%] Ex. 9c - 30° C./75% RH Initial 2 months 3months 6 months 9 months 12 months Asenapine base 96 95 94 95 94 94Asenapine N-Oxide (Cis) n.d. n.d. n.d. <LOR <LOR 0.10 Asenapine N-Oxide(Trans) n.d. n.d. n.d. <LOR <LOR 0.10 Tetradehydro Asenapine <LOR <LOR<LOR <LOR <LOR 0.11 Other related substances n.d. n.d. <LOR <LOR n.d.<LOR Sum of all related substances 0.00 0.00 0.00 0.00 0.00 0.31 * n.d.= not detected, LOR = Limit of reporting (0.1%)

TABLE 9.10 Detected amounts [%] 1 2 3 6 Ex. 9b - 40° C./75% RH Initialmonth months months months Asenapine base 96  96  95  93  94  AsenapineN-Oxide (Cis) n.d. n.d. n.d. n.d.   0.16 Asenapine N-Oxide (Trans) n.d.n.d. n.d. n.d.   0.14 Tetradehydro Asenapine < LOR < LOR 0.11 < LOR  0.17 Other related substances n.d. n.d. < LOR < LOR   0.15 Sum of allrelated   0.00   0.00   0.11   0.00   0.62 substances * n.d. = notdetected, LOR = Limit of reporting (0.1%)

TABLE 9.11 Detected amounts [%] 3 6 9 12 Ex. 9d - 25° C./60% RH Initialmonths months months months Asenapine base 97  95  96  94  95  AsenapineN-Oxide (Cis) n.d. n.d. < LOR < LOR   0.13 Asenapine N-Oxide (Trans)n.d. n.d. < LOR < LOR   0.13 Tetradehydro Asenapine < LOR < LOR   0.10  0.13   0.12 Other related substances n.d. n.d. < LOR n.d. < LOR Sum ofall related   0.00   0.00   0.10   0.13   0.38 substances * n.d. = notdetected, LOR = Limit of reporting (0.1%)

TABLE 9.12 Detected amounts [%] 3 6 9 12 Ex. 9d - 30° C./75% RH Initialmonths months months months Asenapine base 97  94  96  95  95  AsenapineN-Oxide (Cis) n.d. n.d. < LOR < LOR < LOR Asenapine N-Oxide (Trans) n.d.n.d. < LOR < LOR < LOR Tetradehydro Asenapine < LOR < LOR   0.13   0.12  0.10 Other related substances n.d. < LOR < LOR n.d. < LOR Sum of allrelated   0.00   0.00   0.13   0.12   0.10 substances * n.d. = notdetected, LOR = Limit of reporting (0.1%)

TABLE 9.13 Detected amounts [%] Ex. 9d-40° C./75% RH Initial 1 month 3months 6 months Asenapine base 97 96 94 95 Asenapine N-Oxide (Cis) n.d.n.d. n.d. 0.10 Asenapine N-Oxide (Trans) n.d. n.d. n.d. <LORTetradehydro Asenapine <LOR <LOR <LOR 0.17 Other related substances n.d.n.d. <LOR 0.15 Sum of all related substances 0.00 0.00 0.00 0.42 *n.d. =not detected, LOR = Limit of reporting (0.1%)

TABLE 9.14 Detected amounts [%] 3 6 9 12 Ex. 9e-25° C./60% RH Initialmonths months months months Asenapine base 97 96 97 96 96 AsenapineN-Oxide (Cis) n.d. n.d. <LOR n.d. <LOR Asenapine N-Oxide (Trans) n.d.n.d. <LOR n.d. <LOR Tetradehydro Asenapine n.d. <LOR <LOR <LOR <LOROther related substances n.d. n.d. <LOR n.d. <LOR Sum of all relatedsubstances 0.00 0.00 0.00 0.00 0.00 *n.d. = not detected, LOR = Limit ofreporting (0.1%)

TABLE 9.15 Detected amounts [%] 3 6 9 12 Ex. 9e-30° C./75% RH Initialmonths months months months Asenapine base 97 96 97 95 95 AsenapineN-Oxide (Cis) n.d. n.d. <LOR <LOR 0.15 Asenapine N-Oxide (Trans) n.d.n.d. <LOR <LOR 0.15 Tetradehydro Asenapine n.d. <LOR <LOR <LOR <LOROther related substances n.d. <LOR n.d. n.d. <LOR Sum of all relatedsubstances 0.00 0.00 0.00 0.00 0.30 *n.d. = not detected, LOR = Limit ofreporting (0.1%)

TABLE 9.16 Detected amounts [%] Ex. 9e-40° C./75% RH Initial 1 month 3months 6 months Asenapine base 97 97 95 96 Asenapine N-Oxide (Cis) n.d.n.d. n.d. 0.10 Asenapine N-Oxide (Trans) n.d. n.d. n.d. <LORTetradehydro Asenapine n.d. <LOR <LOR <LOR Other related substances n.d.n.d. n.d. 0.11 Sum of all related substances 0.00 0.00 0.00 0.21 *n.d. =not detected, LOR = Limit of reporting (0.1%)

The stability data show that, in certain embodiments of the invention,the initial stability as well as storage stability have beensubstantially improved when compared to the previously developedreference formulations (e.g. Ref. Ex. 2d), both in terms of the amountof asenapine base (in particular with respect to the amount of asenapinebase remaining after storage) as well as the sum of all related (i.e.possible degradation product) substances.

Examples 10A and B Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 10a and 10b are summarized in Table 10.1 below. Theformulations are based on weight percent, as also indicated in Table10.1.

TABLE 10.1 Ex. 10a Ex. 10b Amt Solids Amt Solids Ingredient (Trade Name)[g] [%] [g] [%] Asenapine base 8.01 10.0 8.00 10.0 Acrylic adhesive inethyl acetate, 135.4 69.7 133.6 69.8 ethanol, heptanes and methanol,with a titanium cross-linking agent. Solids content of 41.2% (Ex. 10a)or 41.9% (Ex. 10b) by weight (Duro-Tak ™ 387-2516) Polyvinylpyrrolidone(Povidone K30) 8.00 10.0 8.00 10.0 α-Tocopherol 0.07 0.09 0.04 0.05Ascorbyl palmitate (10% sol. 1.60 0.20 1.61 0.20 in ethanol denat,containing 1% (v/v) methyl ethyl ketone) Sodium metabisulfite (30% aq.sol.) 0.08 0.03 — — Medium chain triglycerides 8.01 10.0 8.01 10.0(Miglyol 812N) Ethanol denat. (1% (v/v) 32.4 — 34.3 — methyl ethylketone) Total 193.6 100.0 193.6 100.0 Area weight [g/m²] 135.9 137.2Asenapine content [mg/cm²] 1.359 1.372

Preparation of the Coating Composition

For Example 10a, a beaker was loaded with a part of the ethanol, thesodium metabisulfite solution was added dropwise under stirring and themixture stirred at least 10 min, before the α-Tocopherol was addeddropwise under stirring. For Example 10b, a beaker was loaded with theα-Tocopherol as well as a part of the ethanol. To this mixturecomprising α-Tocopherol (Example 10b) and sodium metabisulfite (Example10a) in ethanol, the ascorbyl palmitate solution was added dropwiseunder stirring and the resulting mixture stirred for at least 20 min.After adding the medium chain triglycerides under stirring,polyvinylpyrrolidone was weighed in a beaker and added to the mixtureunder stirring. The acrylic pressure sensitive adhesive Duro-Tak™387-2516 was weighed into the reaction mixture, the resulting mixturewas stirred and allowed to stand, after which the asenapine was weighedin a beaker and added to the mixture with the remaining part of theethanol. The mixture was stirred until a clear solution was obtained.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 135.9 g/m² (Example 10a) and 137.2 g/m² (Example 11b), respectively.The dried film was laminated with a polyethylene terephthalate backinglayer (23 μm thickness) to provide an asenapine-containing self-adhesivelayer structure.

Preparation of the TTS

See Example 1.

Stability Measurements

A long term storage stability test was conducted for Examples 10a and10b under different test conditions, i.e. storage at 25° C. and 60%relative humidity (RH), at 30° C. and 75% RH, and at 40° C. and 75% RH.At different time points, samples were taken from the TTS, extractedwith an appropriate extraction solvent and the amount of asenapine base,as well as various possible degradation substances was determined by aspecific quantitative HPLC method with a UV photometric detector, basedon the asenapine content calculated from the (actual) area weight of thetested TTS. The results are shown in Tables 10.2 to 10.7. A plot of thesum of all related (i.e. possible degradation product) substances isshown in FIGS. 10a to 10c in comparison to Example 9a, and in comparisonto Reference Example 2d (for storage at 25° C. and 60% RH as well as at40° C. and 75% RH).

TABLE 10.2 Detected amounts [%] 3 6 9 12 Ex. 10a-25° C./60% RH Initialmonths months months months Asenapine base 97 96 97 96 96 AsenapineN-Oxide (Cis) n.d. n.d. 0.18 0.16 0.26 Asenapine N-Oxide (Trans) n.d.n.d. 0.16 0.15 0.26 Tetradehydro Asenapine n.d. <LOR <LOR <LOR <LOROther related substances n.d. n.d. <LOR n.d. <LOR Sum of all relatedsubstances 0.00 0.00 0.34 0.31 0.52 *n.d. = not detected, LOR = Limit ofreporting (0.1%)

TABLE 10.3 Detected amounts [%] 3 6 9 12 Ex. 10a-30° C./75% RH Initialmonths months months months Asenapine base 97 95 96 96 96 AsenapineN-Oxide (Cis) n.d. <LOR 0.13 0.18 0.31 Asenapine N-Oxide (Trans) n.d.<LOR 0.13 0.16 0.31 Tetradehydro Asenapine n.d. <LOR <LOR <LOR <LOROther related substances n.d. <LOR n.d. n.d. <LOR Sum of all relatedsubstances 0.00 0.00 0.26 0.34 0.62 *n.d. = not detected, LOR = Limit ofreporting (0.1%)

TABLE 10.4 Detected amounts [%] Ex. 10a-40° C./75% RH Initial 1 month 3months 6 months Asenapine base 97 98 95 96 Asenapine N-Oxide (Cis) n.d.n.d. 0.11 0.21 Asenapine N-Oxide (Trans) n.d. n.d. <LOR 0.20Tetradehydro Asenapine n.d. <LOR <LOR <LOR Other related substances n.d.n.d. n.d. <LOR Sum of all related substances 0.00 0.00 0.11 0.41 *n.d. =not detected, LOR = Limit of reporting (0.1%)

TABLE 10.5 Detected amounts [%] Ex. 10b-25° C./60% RH Initial 3 months 6months Asenapine base 96 95 96 Asenapine N-Oxide (Cis) 0.10 0.17 0.20Asenapine N-Oxide (Trans) 0.10 0.16 0.18 Tetradehydro Asenapine <LOR<LOR 0.13 Other related substances n.d. n.d. n.d. Sum of all relatedsubstances 0.20 0.33 0.51 *n.d. = not detected, LOR = Limit of reporting(0.1%)

TABLE 10.6 Detected amounts [%] 1 2 3 6 Ex. 10b-30° C./75% RH Initialmonth months months months Asenapine base 96 97 95 96 96 AsenapineN-Oxide (Cis) 0.10 <LOR 0.10 0.20 0.21 Asenapine N-Oxide (Trans) 0.10n.d. <LOR 0.19 0.19 Tetradehydro Asenapine <LOR n.d. <LOR <LOR 0.15Other related substances n.d. n.d. <LOR n.d. n.d. Sum of all relatedsubstances 0.20 0.00 0.10 0.39 0.55 *n.d. = not detected, LOR = Limit ofreporting (0.1%)

TABLE 10.7 Detected amounts [%] 1 2 3 6 Ex. 10b-40° C./75% RH Initialmonth months months months Asenapine base 96 97 96 96 95 AsenapineN-Oxide (Cis) 0.10 <LOR 0.13 0.22 0.32 Asenapine N-Oxide (Trans) 0.10<LOR 0.12 0.21 0.28 Tetradehydro Asenapine <LOR <LOR <LOR <LOR 0.19Other related substances n.d. <LOR <LOR n.d. <LOR Sum of all relatedsubstances 0.20 0.00 0.25 0.43 0.79 *n.d. = not detected, LOR = Limit ofreporting (0.1%)

The stability data show that an improved stability and also storagestability can be achieved by a combination of α-tocopherol and ascorbylpalmitate, and that addition of a certain amount of sodium metabisulfitehas a positive impact on the overall storage stability.

Example 11A and Reference Examples 11B, 11C and 11D Coating Composition

The formulations of the asenapine-containing coating compositions ofExample 11a as well as Reference Examples 11b, 11c and 11d aresummarized in Table 11.1 below. The formulations are based on weightpercent, as also indicated in Table 11.1.

TABLE 11.1 Ex. 11a Ref. Ex. 11b Ref. Ex. 11c Ref. Ex. 11d Amt Solids AmtSolids Amt Solids Amt Solids Ingredient (Trade Name) [g] [%] [g] [%] [g][%] [g] [%] Asenapine base 2.90 10.0 — — — — — — Asenapine maleate — —7.50 50.0 1.80 12.0 2.12 13.8 Sodium hydroxide (10% — — 14.9 9.95 — —4.20 2.75 sol. in ethanol) Sodium hydrogen carbonate — — — — 0.75 5.03 —— Acrylic adhesive in ethyl 47.5 69.5 14.2 40.1 29.4 82.9 23.1 63.9acetate, ethanol, heptanes and methanol, with a titanium cross-linkingagent. Solids content - 42.4% by wt. (Duro-Tak ™ 387-2516)Polyvinylpyrrolidone 2.90 10.0 — — — — 1.50 9.80 (Povidone K30)α-Tocopherol 0.04 0.14 — — — — — — Ascorbyl palmitate (10% 0.58 0.19 — —— — — — sol. in ethanol denat, containing 1% (v/v) methyl ethyl ketone)Sodium metabisulfite (30% 0.10 0.11 — — — — — — aq. solution) Mediumchain triglycerides 2.90 10.0 — — — — 1.50 9.77 (Miglyol 812 N) Ethanoldenat. (1% (v/v) 12.9 — 15.1 — 4.30 — 4.56 — methyl ethyl ketone) Total69.8 100.0 51.7 100.0 36.3 100.0 37.0 100.0 Area weight [g/m²] 145.3 —153.4 144.3 Asenapine content [mg/cm²] 1.453 — 1.312 1.417

Preparation of the coating composition

The coating composition of Example 11 a was prepared as described forExamples 9d and 10a.

For Reference Example 11b, a beaker was loaded with the asenapinemaleate, the sodium hydroxide solution was added and the mixturestirred. As the mixture solidified, ethanol was added and the mixturefurther stirred. The acrylic pressure sensitive adhesive Duro-Tak™387-2516 was weighed into the reaction mixture, which was then stirredand allowed to stand, and stirred again. The resulting mixture wasinhomogeneous so that coating of the composition was impossible.

For Reference Example 11c, a beaker was loaded with the asenapinemaleate and the ethanol was added. The acrylic pressure sensitiveadhesive Duro-Tak™ 387-2516 was weighed into the reaction mixture, whichwas then stirred and allowed to stand, and stirred again until a clearsolution including undissolved particles was obtained.

For Reference Example 11d, a beaker was loaded with the asenapinemaleate and the sodium hydrogen carbonate. The ethanol was added and theacrylic pressure sensitive adhesive

Duro-Tak™ 387-2516 was weighed into the reaction mixture, which was thenstirred. The polyvinylpyrrolidone was weighed in a beaker and added tothe mixture under stirring. The sodium hydroxide solution and the mediumchain triglycerides were added dropwise and consecutively in this order.A white, homogeneous solution was obtained.

Coating of the Coating Composition, Example 11a and Reference Examples11c and 11d

See Reference Example 1a and Reference Example 1b for the coatingprocess. The coating thickness gave an area weight of the matrix layerof 145.3 g/m² (Example 11a), 153.4 g/m² (Reference Example 11c) and144.3 g/m² (Reference Example 11d), respectively. The dried film waslaminated with a polyethylene terephthalate backing layer (23 μmthickness) to provide an asenapine-containing self-adhesive layerstructure. As outlined above, coating was impossible for ReferenceExample 11b. The coated matrix layer of Reference Example 11c wasvisibly inhomogeneous, likely due to the undissolved sodium hydrogencarbonate particles and adhesion appeared to be insufficient. The coatedmatrix layer of Example 11a showed excellent adhesion, while the coatedmatrix layer of Reference Example 11d exhibited only moderate adhesion.

Preparation of the TTS

See Example 1. FIG. 11e to 11g show pictures of the prepared TTSaccording to Example 11a, Reference Example 11c and Reference Example11d, respectively. From these figures, it can be seen that the TTSsurface of Examples 11a and Reference Example 11d is smooth, while theTTS surface of Reference Example 11b is rough, suggesting aninhomogeneous matrix layer.

Stability Measurements

The initial stability as well as the stability after 1 month storage at40° C. and 75% RH of the TTS of Example 11 a as well as ReferenceExamples 11c and 11d was investigated. Samples were taken from the TTSimmediately after preparation of the TTS and after 1 month storage time,extracted with an appropriate extraction solvent and the amount ofasenapine base, as well as various possible degradation substances wasdetermined by a specific quantitative HPLC method with a UV photometricdetector, based on the asenapine content calculated from the (actual)area weight of the tested TTS. The results are shown in Tables 11.2 and11.3 as well as in FIGS. 11a and 11 b.

TABLE 11.2 Detected amounts [%] Initial stability measurement Ex. 11aRef. Ex. 11c Ref. Ex. 11d Asenapine base 97 97 97 Asenapine N-Oxide(Cis) <LOR <LOR 0.18 Asenapine N-Oxide (Trans) <LOR <LOR 0.20Tetradehydro Asenapine <LOR <LOR <LOR Other related substances n.d. n.d.<LOR Sum of all related substances 0.00 0.00 0.38 *n.d. = not detected,LOR = Limit of reporting (0.1%)

TABLE 11.3 Stored for 1 month Detected amounts [%] at 40° C./75% RH Ex.11a Ref. Ex. 11c Ref. Ex. 11d Asenapine base 95 96 93 Asenapine N-Oxide(Cis) <LOR <LOR 0.59 Asenapine N-Oxide (Trans) <LOR <LOR 0.67 DeschloroAsenapine n.d. <LOR <LOR Tetradehydro Asenapine <LOR <LOR 0.15 Otherrelated substances <LOR n.d. 0.27 Sum of all related substances 0.000.00 1.68 *n.d. = not detected, LOR = Limit of reporting (0.1%)

These data demonstrate that the inventive formulation is able tostabilize the asenapine free base by using a combination of α-tocopheroland ascorbyl palmitate, and that the stability obtained in such a way iseven higher than formulations relying on an in situ production of theasenapine free base from the more stable asenapine maleate salt by wayof deprotonation with sodium hydroxide (Ref. Ex. 11d).

In situ production of the free base form of the active agent is believedto be disadvantageous due to the reduced permeability of the salt form,which is why the in vitro skin permeation behavior of formulations basedon asenapine maleate can be lower, assumedly depending on the timing ofthe deprotonation reaction (see measurement of skin permeation ratebelow).

In addition, as Reference Examples 11b and 11c demonstrate, the use ofdeprotonating agents such as sodium bicarbonate or sodium hydroxide alsoleads to coating compositions getting difficult (see FIG. 11c ) or evenimpossible to formulate so that no TTS can be obtained (Ref. Ex. 11b).

Measurement of Skin Permeation Rate

The permeated amount and the corresponding skin permeation rates of TTSprepared according to Example 11 a as well as Reference Examples 11c and11 d were determined by in vitro experiments in accordance with the OECDGuideline (adopted Apr. 13, 2004) carried out with a 7.0 ml Franzdiffusion cell. Split thickness human skin from cosmetic surgeries(abdomen, date of birth 1964) was used. A dermatome was used to prepareskin to a thickness of 800 μm, with an intact epidermis for all TTS.Diecuts with an area of 1.157 cm² were punched from the TTS. Theasenapine permeated amount in the receptor medium of the Franz cell(phosphate buffer solution pH 5.5 with 0.1% saline azide asantibacteriological agent) at a temperature of 32±1° C. was measured andthe corresponding skin permeation rate calculated. The results are shownin Table 11.4 and FIG. 11c .

TABLE 11.4 Skin permeation rate with SD [μg/(cm² h)] Elapsed Ex. 11a (n= 3) Ref. Ex. 11c (n = 3) Ref. Ex. 11d (n = 3) time [h] Rate SD Rate SDRate SD 4 0.10 0.04 0.07 n.a. — — 8 2.00 0.45 0.48 0.06 0.64 0.28 126.90 1.02 1.02 0.12 3.16 1.00 24 11.07 1.29 1.28 0.17 8.02 1.44 36 15.671.02 1.74 0.25 12.43 1.87 48 15.32 0.58 1.99 0.14 12.70 1.00 60 13.831.06 2.11 0.10 11.25 1.86 72 11.24 0.29 2.25 0.23 10.78 0.29 84 9.200.13 2.41 0.13 8.61 0.58 96 7.22 0.20 2.43 0.13 7.51 0.67 *: Standarddeviation in this Example was, as in all other Examples, calculatedbased on the n-method.

Utilization of Asenapine

The utilization of asenapine at 72 hours was calculated based on thecumulative permeated amount at 72 hours and the initial asenapinecontent. The results are shown in Table 11.5 and in FIG. 11d .

TABLE 11.5 Utilization of asenapine after 72 hours [%] Example 11a Ref.Example 11c Ref. Example 11d (n = 3) (n = 3) (n = 3) 57.9 9.0 47.8

The in vitro experiments show that the good skin permeation rate as wellas the utilization of asenapine of the previously developed referenceformulations (Ref. Ex. 1b and 1c) could be surprisingly maintained forExample 11a, which represents a formulation in accordance with thepresent invention and which provides improved stability (see above andFIGS. 11a and 11b ). While Reference Example lld was able to provide alittle lower, but still acceptable skin permeation rate, the stabilityfor Reference Example 11d was inacceptable (see above). On the otherhand, Reference Example 11c does not provide an acceptable skinpermeation rate (see FIG. 11c ) and the asenapine utilization is alsovery low (Table 11.5 above as well as FIG. 11d ).

The inventive formulations are able to provide improved stability, bothin terms of asenapine degradation as well as asenapine content, whilemaintaining an excellent skin permeation rate.

Examples 12A-C Coating Composition

The formulations of the asenapine-containing coating compositions ofExamples 12a to 12c are summarized in Table 12.1 below. The formulationsare based on weight percent, as also indicated in Table 12.1.

TABLE 12.1 Ex. 12a Ex. 12b Ex. 12c Amt Solids Amt Solids Amt SolidsIngredient (Trade Name) [g] [%] [g] [%] [g] [%] Asenapine base 50.0 10.050.0 10.0 50.0 10.0 Acrylic adhesive in ethyl acetate. 894.3 69.1 892.869.0 895.8 69.3 Solids content ~38.7% by wt. (Duro-Tak ™ 387-4287)Aluminium acetylacetonate 2.30 0.46 2.30 0.46 2.30 0.46Polyvinylpyrrolidone (Povidone 50.4 10.0 49.9 10.0 50.0 10.0 K30)α-Tocopherol 0.25 0.05 0.25 0.05 0.26 0.05 Ascorbyl palmitate (10% sol.in 10.0 0.20 20.1 0.40 10.0 0.20 ethanol denat, containing 1% (v/v)methyl ethyl ketone) Sodium metabisulfite (30% aq. 1.86 0.11 1.90 0.110.46 0.03 solution) Medium chain triglycerides 50.2 10.0 50.0 10.0 50.010.0 (Miglyol 812 N) Ethanol denat. (1% (v/v) methyl 241.9 — 226.5 —247.3 — ethyl ketone) Total 1301.2 100.0 1293.8 100.0 1306.1 100.0 Areaweight [g/m²] 139.9-149.7 142.0-147.5 138.2-143.3 Asenapine content[mg/cm²] 1.399-1.497 1.420-1.475 1.382-1.433

Preparation of the Coating Composition

A stainless steel vessel was loaded with a part of the ethanol, thesodium metabisulfite solution was added dropwise under stirring and themixture stirred at least 10 min. The α-Tocopherol and the ascorbylpalmitate solution were added dropwise under stirring and the resultingmixture stirred for at least 20 min. After adding the medium chaintriglycerides under stirring, polyvinylpyrrolidone was weighed in abeaker and added to the mixture under stirring. The acrylic pressuresensitive adhesive Duro-Tak™ 387-4287 was weighed into the reactionmixture, the resulting mixture was stirred and allowed to stand, afterwhich the aluminium acetylacetonate and the asenapine were each weighedin a beaker and added to the mixture with the remaining part of theethanol. The mixture was stirred until a homogeneous solution wasobtained.

Coating of the Coating Composition

See Reference Example 1a and Reference Example 1b for the coatingprocess. Different films with an area weight of between 139.9 and 149.7g/m² (Ex. 12a), 142.0 and 147.5 g/m² (Ex. 12b) and 138.2 and 143.3 g/m²were produced. The dried film was laminated with a polyethyleneterephthalate backing layer (23 μm thickness) to provide anasenapine-containing self-adhesive layer structure.

Preparation of the TTS

See Example 1.

Stability Measurements

A long term storage stability test was conducted for Examples 12a to 12cunder different test conditions, i.e. storage at 25° C. and 60% relativehumidity (RH), at 30° C. and 75% RH, and at 40° C. and 75% RH. Atdifferent time points, samples were taken from the TTS, extracted withan appropriate extraction solvent and the amount of asenapine base, aswell as various possible degradation substances was determined by aspecific quantitative HPLC method with a UV photometric detector, basedon the asenapine content calculated from the (actual) area weight of thetested TTS. The results are shown in Tables 12.2 to 12.10 as well asFIGS. 12a to 12f , wherein FIGS. 12a to 12c depict the sum of possibledegradation substances detected in comparison to Reference Example 2d(for storage at 25° C. and 60% RH as well as at 40° C. and 75% RH) , andFIGS. 12d to 12f depict the amount of asenapine base in comparison toExample 9a, and in comparison to Reference Example 2d (where data isavailable).

TABLE 12.2 Detected amounts [%] Ex. 12a-25° C./60% RH Initial† 1 month 3months 6 months Asenapine base 98 99 99 99 Asenapine N-Oxide (Cis) 0.21n.d. n.d. n.d. Asenapine N-Oxide (Trans) 0.22 n.d. n.d. n.d.Tetradehydro Asenapine <LOR n.d. <LOR <LOR Other related substances n.d.n.d. n.d. n.d. Sum of all related substances 0.43 0.00 0.00 0.00 *n.d. =not detected, LOR = Limit of reporting (0.1%) †Due to a systematic errorin the HPLC analysis (artefact peaks), the initial values are too highand not reliable

TABLE 12.3 Detected amounts [%] 1 2 3 6 Ex. 12a-30° C./75% RH Initial†month months months months Asenapine base 98 99 98 100 99 AsenapineN-Oxide (Cis) 0.21 n.d. n.d. n.d. 0.12 Asenapine N-Oxide (Trans) 0.22n.d. n.d. n.d. 0.12 Tetradehydro Asenapine <LOR <LOR <LOR <LOR <LOROther related substances n.d. n.d. n.d. n.d. <LOR Sum of all related0.43 0.00 0.00 0.00 0.24 substances * n.d. = not detected, LOR = Limitof reporting (0.1%) †Due to a systematic error in the HPLC analysis(artefact peaks), the initial values are too high and not reliable

TABLE 12.4 Detected amounts [%] 1 2 3 6 Ex. 12a-40° C./75% RH Initial†month months months months Asenapine base 98 99 99 98 98 AsenapineN-Oxide (Cis) 0.21 n.d. n.d. 0.19 0.17 Asenapine N-Oxide (Trans) 0.22n.d. n.d. 0.18 0.18 Tetradehydro Asenapine <LOR <LOR <LOR <LOR <LOROther related substances n.d. n.d. n.d. 0.11 <LOR Sum of all relatedsubstances 0.43 0.00 0.00 0.48 0.35 * n.d. = not detected, LOR = Limitof reporting (0.1%) †Due to a systematic error in the HPLC analysis(artefact peaks), the initial values are too high and not reliable

TABLE 12.5 Detected amounts [%] Ex. 12b-25° C./60% RH Initial† 1 month 3months 6 months Asenapine base 99 99 99 99 Asenapine N-Oxide (Cis) 0.19n.d. <LOR <LOR Asenapine N-Oxide (Trans) 0.20 n.d. <LOR <LORTetradehydro Asenapine <LOR <LOR <LOR <LOR Other related substances n.d.n.d. n.d. <LOR Sum of all related substances 0.39 0.00 0.00 0.00 * n.d.= not detected, LOR = Limit of reporting (0.1%) †Due to a systematicerror in the HPLC analysis (artefact peaks), the initial values are toohigh and not reliable

TABLE 12.6 Detected amounts [%] 1 2 3 6 Ex. 12b-30° C./75% RH Initial†month months months months Asenapine base 99 99 99 99 99 AsenapineN-Oxide (Cis) 0.19 n.d. n.d. <LOR <LOR Asenapine N-Oxide (Trans) 0.20n.d. n.d. <LOR <LOR Tetradehydro Asenapine <LOR <LOR <LOR <LOR <LOROther related substances n.d. n.d. n.d n.d. <LOR Sum of all relatedsubstances 0.39 0.00 0.00 0.00 0.00 * n.d. = not detected, LOR = Limitof reporting (0.1%) †Due to a systematic error in the HPLC analysis(artefact peaks), the initial values are too high and not reliable

TABLE 12.7 Detected amounts [%] 1 2 3 6 Ex. 12b-40° C./75% RH Initial†month months months months Asenapine base 99 99 99 99 99 AsenapineN-Oxide (Cis) 0.19 n.d. <LOR 0.12 0.17 Asenapine N-Oxide (Trans) 0.20n.d. <LOR 0.11 0.18 Tetradehydro Asenapine <LOR <LOR <LOR <LOR 0.11Other related substances n.d. n.d. n.d n.d. <LOR Sum of all relatedsubstances 0.39 0.00 0.00 0.23 0.46 * n.d. = not detected, LOR = Limitof reporting (0.1%) †Due to a systematic error in the HPLC analysis(artefact peaks), the initial values are too high and not reliable

TABLE 12.8 Detected amounts [%] Ex. 12c-25° C./60% RH Initial† 1 month 3months 6 months Asenapine base 98 99 99 99 Asenapine N-Oxide (Cis) 0.21n.d. <LOR 0.15 Asenapine N-Oxide (Trans) 0.22 n.d. <LOR 0.16Tetradehydro Asenapine <LOR <LOR <LOR <LOR Other related substances n.d.n.d. n.d. <LOR Sum of all related substances 0.43 0.00 0.00 0.31 * n.d.= not detected, LOR = Limit of reporting (0.1%) †Due to a systematicerror in the HPLC analysis (artefact peaks), the initial values are toohigh and not reliable

TABLE 12.9 Detected amounts [%] 1 2 3 6 Ex. 12c-30° C./75% RH Initial†month months months months Asenapine base 98 99 99 99 99 AsenapineN-Oxide (Cis) 0.21 n.d. <LOR <LOR 0.14 Asenapine N-Oxide (Trans) 0.22n.d. 0.10 <LOR 0.15 Tetradehydro Asenapine <LOR <LOR <LOR <LOR <LOROther related substances n.d. n.d. n.d. n.d. <LOR Sum of all relatedsubstances 0.43 0.00 0.10 0.00 0.29 * n.d. = not detected, LOR = Limitof reporting (0.1%) †Due to a systematic error in the HPLC analysis(artefact peaks), the initial values are too high and not reliable

TABLE 12.10 Detected amounts [%] 1 2 3 6 Ex. 12c-40° C./75% RH Initial†month months months months Asenapine base 98 99 98 98 99 AsenapineN-Oxide (Cis) 0.21 <LOR 0.12 0.21 0.22 Asenapine N-Oxide (Trans) 0.22<LOR 0.12 0.20 0.25 Tetradehydro Asenapine <LOR <LOR <LOR <LOR 0.10Other related substances n.d n.d. n.d. <LOR <LOR Sum of all relatedsubstances 0.43 0.00 0.24 0.41 0.57 * n.d. = not detected, LOR = Limitof reporting (0.1%) †Due to a systematic error in the HPLC analysis(artefact peaks), the initial values are too high and not reliable

The stability data of Examples 12a-c show that the use of certainacrylic polymers lead to excellent initial as well as storage stabilityof the asenapine formulations, in particular in terms of the amount ofasenapine base remaining after storage.

In Vivo Clinical Study In Vivo Clinical Study

An in vivo clinical trial was conducted to investigate the relativebioavailability of asenapine after transdermal application of the TTS ofReference Examples 2c and 2d compared to sublingual administration. Thestudy was performed in accordance with the ethical principles that havetheir origin in the Declaration of Helsinki.

Trial Design

The trial was conducted in a single center, Phase I, open-label designwith 3 treatments, 3 treatment periods, a fixed treatment sequence in 16healthy male and female subjects, comparing the relative bioavailabilityof asenapine in plasma after single dose transdermal application of theTTS prepared in Reference Examples 2c and 2d to the currently marketedsublingual tablets (Sycrest®, 5 mg).

For each subject, the trial consisted of:

-   An ambulant screening period in which informed consent was obtained    and eligibility of the subjects assessed. Depending on the outcome    of the screening, subjects were included in the trial.-   A treatment and observation period consisting of 3 sequential    treatment periods (each several days long).-   An ambulant follow-up visit after the end of last treatment.

Regarding the 3 sequential treatment periods, the subjects receivedsublingual tablets of 5 mg asenapine b.i.d. (=twice daily) (Reference)on the first day of period 1, a single dose of the TTS prepared inReference Example 2c (3 TTS of 10 cm² each) during period 2 and a singledose of the TTS prepared in Reference Example 2d (1 TTS of 15 cm²)during period 3.

Selection of Trial Population

Only subjects meeting all inclusion and none of the exclusion criteriawere included into the treatment phase. The criteria were assessed atscreening and a re-check was performed on Day -1 of Period 1.

Inclusion Criteria

Subjects had to fulfill all of the following criteria to be eligible forparticipation in the treatment period.

-   1. Subjects who are able to understand and follow instructions    during the study.-   2. Signed informed consent.-   3. White.-   4. Age ≥18 and ≥55 years.-   5. Nonsmoker.-   6. In general good physical health as determined by medical and    surgical history, physical examination, 12-lead electrocardiogram    (ECG), vital signs, and clinical laboratory tests.-   7. Weight within the normal range according to accepted values for    the body mass index (BMI) within 18.0 to 29.4 kg/m².-   8. Normal blood pressure (Systolic Blood Pressure (SBP) ≥90≤139    mmHg; Diastolic Blood Pressure ≥55≤89 mmHg) measured after 5 min    rest in supine position.-   9. A pulse rate of ≥50 and ≤99 b/min measured after 5 min rest in    supine position.-   10. ECG recording without clinically significant abnormalities.-   11. Having had no febrile or infectious illness for at least 7 days    prior to the first administration.

Exclusion Criteria

To ensure that the subjects are healthy and in a comparable status, thefollowing exclusion criteria were applied.

Lifestyle Restrictions

-   1. Demonstrating excess in xanthine consumption (more than 5 cups of    coffee or equivalent per day).-   2. More than moderate alcohol consumption (>35 g of ethanol    regularly per day or >245 g regularly per week).-   3. Any history of alcohol or drug abuse.-   4. Vegetarian.-   5. Positive drug screen.-   6. Positive alcohol breath test.-   7. Consumption of xanthine-containing food or beverages as well as    grapefruit juice or Seville oranges within 48 hours before first    dosing.-   8. Consumption of char-grilled food, broccoli, or Brussel sprouts    within 72 hours before first dosing.

Prior Medication

-   9. Use of any medication (self-medication or prescription    medication) except hormonal contraception within 4 weeks before    first dosing (or at least 10 times the respective elimination    half-life, whichever is longer).

Medical and Surgical History

-   10. Demonstrating any active physical disease, acute or chronic.-   11. Any history of drug hypersensitivity, asthma, urticaria or other    severe allergic diathesis as well as current hay fever.-   12. Any history of hypersensitivity of any component of the    investigated dosage forms.-   13. Any history of chronic gastritis or peptic ulcers.-   14. Any history of chronic or recurrent metabolic, renal, hepatic,    pulmonary, gastrointestinal, neurological (esp. history of epileptic    seizures), endocrinological (esp. diabetes mellitus), immunological,    psychiatric or cardiovascular disease, myopathies, dermal diseases,    and bleeding tendency.-   15. Gilbert syndrome.-   16. Any gastrointestinal complaints within 7 days prior to first    dosing.-   17. Any scars, moles, tattoos, skin irritation or excessive hair    growth at the TTS application site.-   18. Any suicidal ideation of type 2 to 5 on the C-SSRS (Columbia    Suicidal Severity Rating Scale) in the past 12 months (i.e., active    suicidal thought, active suicidal thought with method, active    suicidal thought with intent but without specific plan, or active    suicidal thought with plan and intent).

Laboratory Examinations

-   19. Laboratory values outside the reference range that are of    clinical relevance (e.g., suggesting an unknown disease and    requiring further clinical evaluation assessed by the investigator),    especially regarding aspartate aminotransferase (AST), alanine    aminotransferase (ALT), gamma glutamyl transpeptidase (GGT).-   20. Positive test for human immunodeficiency virus (HIV)    antibodies/p24 antigen.-   21. Positive Hepatitis B-virus surface antigen (HBsAg) test.-   22. Positive Anti-hepatitis C-virus antibodies (Anti-HCV) test.

Other

-   23. Blood donation within 30 days before signing informed consent to    this trial.-   24. Participation in the treatment phase of a clinical study 30 days    or blocked by the follow-up period of a previous clinical trial    before signing informed consent to this trial.-   25. Women of childbearing potential not using a highly effective    method of birth control. Highly-effective methods of birth control    are defined as those which result in a low failure rate, i.e. less    than 1% per year, when used consistently and correctly (e.g.,    combination of intrauterine device and condom). Female subjects are    considered to be of childbearing potential unless surgically    sterilized by hysterectomy or bilateral tubal ligation, or    postmenopausal for at least 2 years.

26. Pregnant or breastfeeding women.

Treatments During the Study

The treatments administered during the study are summarised in Table13.1 below and their characteristics are detailed below.

TABLE 13.1 Dose (Active amount based on label composition Formu- Mode ofTreatment of the dosage form) lation administration Reference 5 mg pertablet sublingual Two administrations (Period 1) tablet b.i.d. (q12h)TTS of Ref. Ex. 3*(8.4 mg/10 cm²) TTS Single administration, 2c (Period2) TTS applied for 3.5 days TTS of Ref. Ex. 21.0 mg/15 cm² TTS Singleadministration, 2d (Period 3) TTS applied for 3.5 days b.i.d. = twicedaily; q12h = every 12 h

The reference formulation administered in period 1 contains the activeingredient asenapine maleate and is marketed under the trade nameSycrest® 5 mg Sublingualtabletten by N.V. Organon, Oss, Netherlands. Thepharmacy central number (PZN) is 07728207.

Administration of the Sublingual Tablets (Reference)

Sublingual tablets were administered in the morning and in the eveningof the first day only with 12 hours in between the two administrationsaccording to the administration instructions given in the summary ofproduct characteristics. The subjects were instructed to place thetablets under the tongue for at least 10 min to allow dissolving of thesublingual tablet and not to chew or swallow the sublingual tablets.

Application of the TTS

The TTS were applied to intact skin on the upper chest or upper back.Hairs on the application area were trimmed with scissors (not shaved)before application, if necessary. The subjects were instructed to verifythat the skin is free of detergents, oils and fat before TTSapplication. The TTS was placed on the desired position and pressed forat least 30 sec with fingers or the palm to fixate the TTS on the skinsurface. In case of need and to avoid further detachment, the TTS wasadditionally fixated with an adhesive overlay free of active agent. Theoptional adhesive overlay was placed above the TTS in such a way thateach side was equally covered by the adhesive overlay. Afterwards, tofixate the TTS, it was pressed again for at least 30 sec with fingers orthe palm. The TTS were removed after 3.5 days (84 hours, Period 2 andPeriod 3). After removal, the used TTS (including the adhesive overlay,if applicable) were handled and stored under nitrogen in therefrigerator until they were further analyzed.

Timing of Dose for Each Subject

On the first day of Period 1, no breakfast was served; the subjectsfasted overnight before morning administration. A standardized lunch wasgiven 4 h and dinner approximately 10 hour after morning administration.Fluid intake was not allowed from 1 hour before until 1 hour aftermorning and evening administration. As food does not interact with theTTS, the subjects received standardized meals and beverages duringin-house days at customary times during Period 2 and 3. During in-housedays, the subjects were only allowed to consume food or beveragesprovided by the study unit.

Restrictions and Precautions

During the trial, subjects were instructed to abstain from allactivities which may increase body temperature, i.e., physical exertion,sauna, environments with great heat. During the time the TTS were worn,subjects were not allowed to perform any activities which may influenceadhesion of the TTS such as any activities which would increasesweating. Further restrictions on food and beverages intakes were placede.g. in accordance with the exclusion criteria.

Sample Collection and Determination of Blood Plasma Concentrations

Blood samples for the determination of the concentration of asenapineand its metabolites in blood plasma were collected at specified timepoints after administration.

A validated internally standardized liquid chromatography tandem massspectrometry method was used for the determination of the blood plasmaconcentration of asenapine, N-desmethyl-asenapine andasenapine-glucuronide, which was carried out by a GLP (Good

Laboratory Practice)—certified laboratory. Plasma concentrations ofasenapine-glucuronide were only determined for 8 subjects, which had noinfluence on the validity of the results, or the interpretation of thetrial results. The lower limits of quantification (LLOQs) were 0.1 ng/mlfor asenapine and N-desmethyl-asenapine in plasma, and 0.25 ng/ml forasenapine-glucuronide.

Adverse Events (AE)

Adverse events were ascertained by the investigator using non-leadingquestions, noted as spontaneously reported by the subjects to themedical staff or observed during any measurements on all study daysafter administration of the dosage form and rated by a study physician.

Furthermore, suicide risk was monitored. All positive reports during thetrial were documented as adverse events. Suicidal ideation of type 1-3was documented as a non-serious AE. Suicidal ideation of type 4 and 5and all suicidal behavior during the trial were documented as a seriousadverse event (SAE) and reported.

An AE was referred to the treatment and time point after which itoccurred, i.e., any AE occurring before the first dosing was counted asbaseline complaint/pre-treatment AE and is not included in the belowanalysis.

Results and Analysis

All 16 subjects completed period 1 (reference) of the trial. Afterperiod 1 (reference) and before commencing period 2 (Ref. Ex. 2c), 1subject dropped out. Another subject dropped out during period 3 (Ref.Ex. 2d), but could be assessed for the adverse events analysis. Safetylaboratory parameters, vital signs, and ECG parameters showed nomedically relevant changes.

The results of the study are shown in Tables 13.2 to 13.9 and FIGS. 13ato 13e .

Arithmetic Mean Blood Plasma Concentration of Asenapine

Arithmetic mean values of the asenapine blood plasma concentration basedon all 16 subjects for period 1 and based on the 15 and 14 subjects thatcompleted periods 2 and 3, respectively, along with the standarddeviation values are presented in Table 13.2 as well as FIGS. 13a and13b . AUC values were calculated from the blood plasma concentration.The t_(tag) was calculated approximatively as the mean arithmetic valueof the first point in time when a measurable (i.e. non-zero) asenapineblood plasma concentration was obtained, and the results also indicatedin Table 13.2.

TABLE 13.2 Asenapine blood plasma concentration [ng/ml] Reference Ref.Ex. 2c Ref. Ex. 2d (n = 16) (n = 15) (n = 14) Time [h] mean SD mean SDmean SD 0 0.00 0.00 0.00 0.00 0.00 0.00 0.5 2.89 1.86 — — — — (n = 15) 13.58 1.68 — — — — 2 3.07 1.10 0.02 0.07 0.02 0.07 4 2.85 1.09 0.56 0.580.47 0.34 6 — — 0.92 0.70 0.86 0.44 8 1.48 0.57 1.63 1.09 1.47 0.63 120.73 0.28 2.13 0.98 1.95 0.67 12.5 3.76 1.65 — — — — 13 4.14 1.90 — — —— 14 3.27 1.56 — — — — 16 2.42 1.12 2.49 1.08 2.23 0.95 20 1.62 0.80 — —— — 24 1.27 0.71 2.93 1.14 2.44 0.80 36 0.39 0.18 1.81 0.61 1.55 0.37 (n= 14) 48 0.30 0.15 2.11 0.59 1.81 0.46 60 0.15 0.12 1.45 0.34 1.31 0.29(n = 14) 72 0.14 0.13 1.67 0.37 1.42 0.36 84 0.06 0.09 1.21 0.22 1.090.26 (n = 14) 86 — — 1.19 0.24 1.02 0.23 88 — — 1.04 0.18 0.88 0.20 960.06 0.09 0.79 0.16 0.68 0.13 108 — — 0.41 0.09 0.36 0.06 120 0.03 0.060.37 0.11 0.30 0.07 132 — — 0.22 0.08 0.19 0.04 144 0.01 0.04 0.20 0.060.17 0.04 156 — — 0.11 0.07 0.09 0.07 168 0.01 0.03 0.11 0.07 0.09 0.07192 — — 0.04 0.06 0.02 0.04 216 — — 0.01 0.03 0.01 0.03 240 — — 0.010.03 0.00 0.00 AUC₍₀₋₄₈₎ — — 95.06 37.20 82.26 25.65 [(ng/ml) h]AUC₍₀₋₇₂₎ — — 135.12 46.05 117.34 33.44 [(ng/ml) h] AUC₍₀₋₈₄₎ 178.44*63.59 152.36 48.81 132.38 36.84 [(ng/ml) h] C_(max) [ng/ml] 4.71 1.682.93 1.14 2.51 0.90 C₄₈ [ng/ml] — — 2.11 0.59 1.81 0.46 C₇₂ [ng/ml] — —1.67 0.37 1.42 0.36 C₈₄ [ng/ml] — — 1.21 0.22 1.09 0.26 t_(lag) [h] 0.50 4.27 1.00 3.71 0.70 Residual amount** 12.0 3.3 10.3 2.3 [mg/total areaof (3*10 cm²) (3*10 cm²) (15 cm²) (15 cm²) release] Mean release — — 3.80.9 3.1 0.6 rate*** [mg/day] *The AUC₍₀₋₈₄₎ value is calculated for thereference period by multiplying the AUC₍₀₋₂₄₎ value by 3.5. **Theresidual amount is determined by extraction of the active from a sampleof the used TTS with an appropriate solvent followed by determination ofthe active amount using a validated HPLC method with a UV photometricdetector. ***The mean release rate is calculated based on the initialasenapine content in the TTS (according to the label composition)applied and on the residual amount in the TTS after 84 hours referringto the total dose administered (see Table 13.1).

Pharmacokinetic Analysis of Asenapine and Metabolites

Based on the plasma concentration time data of asenapine andmetabolites, plasma pharmacokinetic parameters were calculated using noncompartmental procedures and the results are presented in Tables 13.3 to13.5, wherein Cay represents the average concentration observed duringthe relevant dosing interval (12 hours for Period 1/Reference and 84hours for Periods 2 and 3/Reference Examples 2c and 2d), and whereint_(lag) represents the time of first quantifiable concentration afteradministration. For C_(av) and t_(lag) of the Reference formulationmerely the first dosing interval (0-12 hours) was considered. Further,the blood plasma concentration profile of the metabolites asenapineglucuronide and N-desmethyl-asenapine was depicted as geometric meanvalues and indicating the geometric mean multiplied with and divided bythe geometric standard deviation as error bars in FIGS. 13c, 13d and 13e.

The biometrical evaluation was carried out using SAS software, Version9.3 of the SAS

System for windows. Pharmacokinetics calculations were carried out usingPhoenix WinNonlin version 6.4 The pharmacokinetic calculation was basedon all subjects who completed at least 2 treatment periods, i.e., whohave evaluable data for the Reference and at least one of ReferenceExamples 2a or 2b for asenapine and N-desmethyl-asenapine. Thus, thesubject number was n=15 for Periods 1 and 2 (Reference and ReferenceExample 2c) and n=14 for Period 3

(Reference Example 2d). For asenapine-glucuronide, the subject numberwas n=8 for all Periods. Values below LLOQ were excluded from anycalculations for descriptive statistics. Descriptive statistics ofconcentrations were calculated if at least 1/2 of the individual datapoints were measured equal or above LLOQ.

Calculation of the pharmacokinetic characteristics were based on actualblood sampling times [h] (relative to the corresponding administrationtime—accepted deviations from planned blood sampling times were within3,5%) rounded to 2 decimal digits and negative pre dose times set tozero.

At time points in the lag time between time zero and the firstquantifiable concentration, concentrations below LLOQ were calculated aszero. Concentrations below LLOQ between 2 quantifiable concentrationswere calculated with half the LLOQ. Trailing concentrations below LLOQwere not used in calculations.

Descriptive statistics of pharmacokinetic parameters were calculatedseparately for each of the Periods 1, 2 and 3. For tmax, frequencytables were drawn by treatment based on the nominal time of tmax.

For each of Reference and Reference Examples 2c and 2d, pharmacokineticparameters of asenapine and metabolites were compared by means of anexploratory analysis of variance (ANOVA) model. Arithmetic and geometricmeans used for the calculation of point estimators such as differencesor ratios between treatments were derived from the ANOVA as least squaremeans (LSMEANS) or exponential transformed LSMEANS, respectively. Theinclusion of a 90% confidence interval implies a value of a=0.05 for thetype-I error. No α-adjustment was performed.

Based on fundamental pharmacokinetic relationships, the multiplicativemodel was applied for all concentration related parameters. This impliedthat these characteristics were rather log normally than normallydistributed. The ANOVA, therefore, was performed after logarithmictransformation. Exemplary results are shown in Tables 13.6 and 13.7.

The plasma concentration profile of asenapine shows that therapeuticconcentrations may be maintained over the entire wearing period of theTTS without major fluctuations. Compared to sublingual administration,maximum concentrations were lower and reached later after transdermalapplication. The formation of the major metabolites,N-desmethyl-asenapine and asenapine-glucuronide, is markedly reducedcompared to sublingual administration.

TABLE 13.3 Descriptive statistics: geometric means and standarddeviation factors of asenapine blood plasma concentration [ng/ml]Reference Ref. Ex. 2c Ref. Ex. 2d (n = 15) (n = 15) (n = 14) Time [h]Mean SD Mean SD Mean SD 0.5 2.32 2.11 — — — — 1 3.21 1.72 — — — — 2 2.91.47 — — — — 4 2.64 1.52 0.451 2.78 0.337 2.41 6 — — 0.65 2.45 0.7031.81 8 1.37 1.55 1.28 2.08 1.25 1.68 12 0.683 1.57 1.92 1.61 1.76 1.4612.5 3.21 1.78 — — — — 13 3.52 1.85 — — — — 14 2.88 1.7 — — — — 16 2.181.65 2.27 1.55 1.93 1.61 20 1.44 1.68 — — — — 24 1.12 1.76 2.72 1.492.32 1.39 36 0.35 1.57 1.71 1.44 1.51 1.28 48 0.273 1.64 2.03 1.33 1.751.3 60 0.182 1.59 1.41 1.27 1.28 1.25 72 0.183 1.63 1.62 1.28 1.37 1.3184 — — 1.18 1.22 1.06 1.28 86 — — 1.17 1.22 1 1.24 88 — — 1.02 1.2 0.8621.25 96 — — 0.776 1.24 0.665 1.24 108 — — 0.401 1.27 0.352 1.2 120 — —0.35 1.35 0.291 1.28 132 — — 0.223 1.31 0.188 1.26 144 — — 0.194 1.330.163 1.31 156 — — 0.144 1.23 0.129 1.23 168 — — 0.148 1.26 0.132 1.21Key pharmacokinetic characteristics of Asenapine in plasma ReferenceRef. Ex. 2c Ref. Ex. 2d (n = 15) (n = 15) (n = 14) AUC₍₀₋₂₄₎ * 47.4(1.51) 38.6 (1.61) 35.6 (1.46) [(ng/ml) h] 27.3-89.6 22.3-77.5 19.7-72.8AUC₍₂₄₋₄₈₎ * 12.6 (1.66) 49.2 (1.41) 42.7 (1.31) [(ng/ml) h]  5.61-28.327.5-86.8 31.0-67.6 AUC₍₄₈₋₇₂₎ * — 39.0 (1.28) 34.1 (1.27) [(ng/ml) h]24.5-60.7 22.2-51.7 AUC₍₀₋₄₈₎ * 88.2 (1.49) 78.6 (1.36) [(ng/ml) h]49.7-161  51.8-140  AUC₍₀₋₇₂₎ *  128 (1.42)  113 (1.33) [(ng/ml) h]74.2-222  80.3-192  AUC(₀₋₈₄₎ * —  145 (1.39)  128 (1.32) [(ng/ml) h]85.5-245  89.4-215  C_(max) [ng/ml] * 3.47 (1.61) 2.72 (1.49) 2.37(1.41) 1.43-6.88 1.46-5.08 1.56-4.78 C₄₈ [ng/ml] — 2.03 (1.33) 1.75(1.30) 1.27-3.47 1.10-2.65 C₇₂ [ng/ml] — 1.62 (1.28) 1.37 (1.31)1.01-2.26 0.822-2.13  C₈₄ [ng/ml] — 1.18 (1.22) 1.06 (1.28) 0.826-1.61 0.675-1.70  C_(av) [ng/ml] * 1.92 (1.52) 1.72 (1.39) 1.52 (1.32)0.796-3.34  1.02-2.92 1.06-2.56 t_(max) [h] ** 1.03 24.0 24.0 0.5-4.024.0-24.0 16.0-24.1 t_(lag) [h] ** 0.5 4.0 4.0 0.5-1.1 2.0-6.0 2.0-4.0t_(1/2 λz) [h] * 16.5 (1.85) 28.0 (1.38) 27.1 (1.41) 8.18-55.5 16.0-42.717.5-52.7 * AUC, C_(max), C_(av) and t_(1/2 λz) given as geometric mean(Standard deviation), Minimum-Maximum; Standard deviation (SD) given isthe geometric standard deviation factor for both, the descriptivestatistics and key PK characteristics. ** t_(max) and t_(lag) as Median(Minimum-Maximum)

TABLE 13.4 Key pharmacokinetic characteristics of asenapine-glucuronidein plasma Reference Ref. Ex. 2c Ref. Ex. 2d (n = 8) (n = 8) (n = 8)AUC₍₀₋₂₄₎ *  221 (1.41) 44.0 (1.68) 42.6 (1.69) [(ng/ml) h] 147-38322.8-115  23.0-116  AUC₍₂₄₋₄₈₎ * 84.4 (1.35) 92.7 (1.52) 76.6 (1.49)[(ng/ml) h] 51.8-131  64.0-226  54.4-166  AUC₍₀₋₄₈₎ * —  137 (1.56)  120(1.55) [(ng/ml) h] 87.6-340  77.4-281  AUC₍₀₋₇₂₎ * —  220 (1.50)  185(1.50) [(ng/ml) h] 152-521 134-418 AUC₍₀₋₈₄₎ * —  259 (1.48)  214 (1.49)[(ng/ml) h] 183-593 158-478 C_(max) [ng/ml] * 13.4 (1.56) 4.66 (1.54)3.84 (1.45) 7.75-28.0 3.05-11.1 2.68-7.71 t_(max) [h] ** 4.00 36.0 36.04.00-4.05 36.0-83.9 36.0-60.0 t_(lag) [h] ** 1.00 6.01 6.00 1.00-1.034.00-8.00 4.00-8.02 t_(1/2 λz) [h] * 15.9 (1.47) 27.9 (1.38) 21.6 (1.24)8.12-29.2 17.3-50.0 14.4-27.4 * AUC, C_(max) and t_(1/2 λz) given asgeometric mean (Standard deviation), Minimum-Maximum; Standard deviationgiven is the geometric standard deviation factor ** t_(max) and t_(lag)as Median (Minimum-Maximum)

TABLE 13.5 Key pharmacokinetic characteristics of N-desmethyl-asenapinein plasma Reference Ref. Ex. 2c Ref. Ex. 2d (n = 15) (n = 15) (n = 14)AUC₍₀₋₂₄₎ *  11.5 (1.42)  1.67 (2.43)  1.27 (2.16) [(ng/ml) h] 6.34-20.10.452-5.79 0.420-3.87 AUC₍₀₋₄₈₎ * —  9.10 (1.69)  7.51 (1.54) [(ng/ml)h]  4.27-24.1  3.97-16.2 AUC₍₀₋₇₂₎ * —  16.8 (1.62)  14.4 (1.51)[(ng/ml) h]  8.27-42.9  7.79-30.8 AUC₍₀₋₈₄₎ * —  20.3 (1.59)  17.5(1.50) [(ng/ml) h]  10.1-51.5  9.31-38.0 C_(max) [ng/ml] * 0.514 (1.43)0.351 (1.58) 0.310 (1.49) 0.259-0.969  0.173-0.846  0.165-0.634 t_(max)[h] ** 8.00 48.0 60.0 4.00-11.9  36.0-84.1  36.0-72.0 t_(lag) [h] **2.02 16.0 16.0 1.00-4.05  8.00-24.0  12.0-24.1 * AUC and C_(max) givenas geometric mean (Standard deviation), Minimum-Maximum; Standarddeviation given is the geometric standard deviation factor ** t_(max)and t_(lag) as Median (Minimum-Maximum)

TABLE 13.6 90% confidence intervals for log transformed pharmacokineticcharacteristics of asenapine-glucuronide Point Lower Upper estimatelimit of limit of Comparison (%) 90% CI (%) 90% CI (%) AUC₍₀₋₄₈₎ Period2/Reference 44.70 37.04 53.93 Period 3/Reference 39.04 32.35 47.10Period 2/Period 3 114.49 94.90 138.14 C_(max) Period 2/Reference 34.8727.01 45.03 Period 3/Reference 28.74 22.26 37.11 Period 2/Period 3121.34 93.97 156.70

TABLE 13.7 90% confidence intervals for log transformed pharmacokineticcharacteristics of N-desmethyl-asenapine Point Lower Upper estimatelimit of limit of Comparison (%) 90% CI (%) 90% CI (%) AUC₍₀₋₄₈₎ Period2/Reference 41.47 34.95 49.21 Period 3/Reference 33.13 27.80 39.47Period 2/Period 3 125.18 105.05 149.17 C_(max) Period 2/Reference 68.3458.52 79.80 Period 3/Reference 58.77 50.14 68.90 Period 2/Period 3116.28 99.19 136.31

Adverse Events (AE)

Tables 13.8 and 13.9 reflect the number of adverse events reported inthe different categories.

Although treatment duration for the sublingual tablet (Reference) wasonly 12 h (i.e., 2 administrations) compared to 3.5 days TTS application(Reference Examples 2c and 2d), common systemic side effects ofasenapine treatment, such as fatigue and dizziness, were observed lessfrequently after TTS application and, in case of fatigue, only with mildintensity. In comparison to the sublingually administered treatment(Reference), the frequency and intensity of fatigue was notably lowerafter transdermal administration, and dizziness occurred with lowerfrequency.

Oral discomfort symptoms, such as hypoaesthesia and dry mouth, asobserved following the administration of the reference treatment, werenot observed under TTS application (Reference Examples 2c and 2d).

Local tolerance at the application site was good, only mild reactionswere observed occasionally (five AEs) which subsided withoutintervention.

The dysmenorrhea reported during period 3, which was moderate inintensity, had no relationship to the TTS of Reference Example 2dadministered.

No SAE was reported and none of the subjects had suicidal ideations.

Overall, transdermal application of asenapine was safe and welltolerated. The AEs observed after administration of either TTS (Periods2 and 3) were mostly mild and transient, resolved without intervention,and the frequency of AEs was lower compared to the reference period 1.

TABLE 13.8 Adverse events (AE) and serious adverse events (SAE) reportedduring the study Period 1 Period 2 Period 3 (Reference) (Ref. Ex. 2c)(Ref. Ex. 2d) (n = 16) (n = 15) (n = 15) total Mild (AE) 41 26 17 84Moderate (AE) 13 1 2 16 Severe (AE) 3 0 1 4 Serious (SAE) 0 0 0 0 total57 27 20 104 Outcome: Number of 57 27 20 104 subjects recovered

TABLE 13.9 Adverse events (AE) by type of AE Period 1 Period 2 Period 3(Reference) (Ref. Ex. 2c) (Ref. Ex. 2d) (n = 16) (n = 15) (n = 15) totalFatigue* 21 12 11 44 (8/11/2) (11/1/0) (10/1/0) Dizziness 11 2 2 15Hypoaesthesia oral 12 0 0 12 Gastrointestinal 5 1 0 6 disorders(Abdominal pain upper, constipation, diarrhoea, dry mouth) Other generaldisorders 1 6 2 9 and administration site conditions Musculoskeletal 1 00 1 and connective tissue disorders (pain in extremity) Other nervoussystem 6 6 4 16 disorders (akathisia, head discomfort, headache,paraesthesia, presyncope) Dysmenorrhoea 0 0 1 1 total 57 27 20 104*Numbers in parentheses indicate incidences by intensity(mild/moderate/severe)

The Invention Relates in Particular to the Following Further Items:

-   1. Transdermal therapeutic system for the transdermal administration    of asenapine comprising a self-adhesive layer structure containing a    therapeutically effective amount of asenapine, said self-adhesive    layer structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1. asenapine;        -   2. a polymer selected from acrylic polymers;        -   3. an additional polymer; and        -   4. α-tocopherol in an amount of from 0.01 to 2% of the            matrix layer composition and ascorbyl palmitate in an amount            of at least 0.01% of the matrix layer composition as            stabilizers.-   2. Transdermal therapeutic system according to item 1, wherein the    matrix layer composition further comprises sodium metabisulfite in    an amount of from 0 to 0.5%, preferably from 0.01 to 0.2%, and more    preferably from 0.05 to 0.15% of the matrix layer composition as    stabilizer.-   3. Transdermal therapeutic system according to item 2, wherein the    matrix layer composition further comprises sodium metabisulfite in    an amount of about 0.1% of the matrix layer composition as    stabilizer.-   4. Transdermal therapeutic system according to any one of items 1 to    3, wherein the matrix layer composition comprises α-tocopherol in an    amount of at least 0.025% of the matrix layer composition, and/or-   wherein the matrix layer composition comprises α-tocopherol in an    amount of up to 1.5% or 0.75%, preferably up to 0.5%, and more    preferably up to 0.1% of the matrix layer composition.-   5. Transdermal therapeutic system according to item 4, wherein the    matrix layer composition comprises α-tocopherol in an amount of    about 0.05% of the matrix layer composition.-   6. Transdermal therapeutic system according to any one of items 1 to    5, wherein the matrix layer composition comprises ascorbyl palmitate    in an amount of at least 0.02%, preferably at least 0.08%, and more    preferably at least 0.15% of the matrix layer composition, and/or-   wherein the matrix layer composition comprises ascorbyl palmitate in    an amount of up to 2.0 or 1.0%, and preferably up to 0.6% of the    matrix layer composition.-   7. Transdermal therapeutic system according to item 6, wherein the    matrix layer composition comprises ascorbyl palmitate in an amount    of from 0.2% to 0.4% of the matrix layer composition.-   8. Transdermal therapeutic system according to any one of items 1 to    7, wherein the additional polymer is selected from polymers which    provide for an improved water and/or moisture absorption of the    matrix layer, and more preferably from polyvinylpyrrolidones, and    most preferably from soluble polyvinylpyrrolidones.-   9. Transdermal therapeutic system according to item 8, wherein the    additional polymer is a polyvinylpyrrolidone having a K-Value within    a range selected from the group of ranges consisting of    -   9 to 15, and preferably 10.2 to 13.8,    -   15 to 20, and preferably 15.3 to 18.4,    -   20 to 27, and preferably 22.5 to 27.0,    -   27 to 35, and preferably 27.0 to 32.4, and    -   75 to 110, and preferably 81.0 to 97.2,-   or any mixtures thereof, and preferably is a polyvinylpyrrolidone    having a K-Value within a range of 27.0 to 32.4 or of 81.0 to 97.2    or any mixtures thereof, and more preferably is a    polyvinylpyrrolidone having a K-Value within range of 27.0 to 32.4.

10. Transdermal therapeutic system according to item 8 or 9, wherein thematrix layer composition comprises an additional polymer selected frompolyvinylpyrrolidones, and preferably from solublepolyvinylpyrrolidones, in an amount of from 0 to 20% of the matrix layercomposition, preferably from 5 to 15% of the matrix layer compositionand more preferably in an amount of about 10% of the matrix layercomposition.

-   11. Transdermal therapeutic system according to any one of items 1    to 10, wherein the transdermal therapeutic system contains at least    0.70 mg/cm², preferably at least 0.80 mg/cm², more preferably at    least 0.82 mg/cm² and most preferably at least 0.83 mg/cm²    asenapine.-   12. Transdermal therapeutic system according to any one of items 1    to 11, wherein the transdermal therapeutic system contains from 0.70    mg/cm² to 4.0 mg/cm², preferably from 0.80 mg/cm² to 3.0 mg/cm²,    more preferably from 0.82 mg/cm² to 2.0 mg/cm² and most preferably    from 0.83 mg/cm² to 1.7 mg/cm² asenapine.-   13. Transdermal therapeutic system according to any one of items 1    to 12, wherein the area weight of the matrix layer ranges from 90 to    230 g/m², preferably from 110 to 210 g/m², and most preferably from    120 to 170 g/m².-   14. Transdermal therapeutic system according to any one of items 1    to 13, wherein the transdermal therapeutic system provides by    transdermal delivery a mean release rate of 0.5 to 20 mg/day over at    least 48 hours, preferably over 72 hours, and more preferably over    84 hours of administration.-   15. Transdermal therapeutic system according to item 14, wherein the    transdermal therapeutic system provides by transdermal delivery a    mean release rate of 0.5 to 20 mg/day, preferably 1.0 to 15 mg/day,    more preferably of 2.0 to 10 mg/day over at least 48 hours of    administration, or-   wherein the transdermal therapeutic system provides by transdermal    delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to    15 mg/day, more preferably of 2.0 to 10 mg/day over at least 72    hours of administration, or-   wherein the transdermal therapeutic system provides by transdermal    delivery a mean release rate of 0.5 to 20 mg/day, preferably 1.0 to    15 mg/day, more preferably of 2.0 to 10 mg/day over 84 hours of    administration.-   16. Transdermal therapeutic system according to any one of items 1    to 15, wherein the transdermal therapeutic system provides by    transdermal delivery an AUC₀₋₄₈ from 20 to 300 (ng/ml) h or from    more than 300 to 450 (ng/ml) h, and preferably provides by    transdermal delivery an AUC₀₋₄₈ from 30 to 200 (ng/ml) h.-   17. Transdermal therapeutic system according to any one of items 1    to 16, wherein the transdermal therapeutic system provides by    transdermal delivery an AUC₀₋₇₂ from 30 to 400 (ng/ml) h or from    more than 400 to 600 (ng/ml) h, and preferably provides by    transdermal delivery an AUC₀₋₇₂ from 50 to 300 (ng/ml) h.-   18. Transdermal therapeutic system according to any one of items 1    to 17, wherein the transdermal therapeutic system provides by    transdermal delivery an AUC₀₋₈₄ from 35 to 450 (ng/ml) h or from    more than 450 to 700 (ng/ml) h, and preferably provides by    transdermal delivery an AUC₀₋₈₄ from 60 to 350 (ng/ml) h.-   19. Transdermal therapeutic system according to any one of items 1    to 18, wherein the transdermal therapeutic system provides by    transdermal delivery a C_(max) to C₄₈ ratio of less than 2.0,    preferably of less than 1.5 and more preferably of less than 1.3.-   20. Transdermal therapeutic system according to any one of items 1    to 19, wherein the transdermal therapeutic system provides by    transdermal delivery a C_(max) to C₇₂ ratio of less than 3.0,    preferably of less than 2.5 and more preferably of less than 2.0.-   21. Transdermal therapeutic system according to any one of items 1    to 20, wherein the transdermal therapeutic system provides by    transdermal delivery a C_(max) to C₈₄ ratio of less than 3.5,    preferably of less than 3.0, more preferably of less than 2.5 and    most preferably of less than 2.0.-   22. Transdermal therapeutic system according to any one of items 1    to 21, wherein the asenapine-containing matrix layer does not    comprise isopropyl palmitate in an amount of 10% of the matrix layer    composition, preferably does not comprise isopropyl palmitate in an    amount of 5 to 15% of the matrix layer composition and most    preferably does not comprise isopropyl palmitate.-   23. Transdermal therapeutic system according to any one of items 1    to 22, wherein the matrix layer composition does not comprise any of    polysiloxanes and polyisobutylenes in an amount of more than 50% of    the matrix layer composition.-   24. Transdermal therapeutic system according to any one of items 1    to 23, wherein the transdermal therapeutic system has an area of    release of from 5 to 100 cm².-   25. Transdermal therapeutic system according to any one of items 1    to 24, wherein the asenapine-containing matrix layer does not    comprise isopropyl myristate in an amount of 5% of the matrix layer    composition, preferably does not comprise isopropyl myristate in an    amount of 1 to 10% of the matrix layer composition and most    preferably does not comprise isopropyl myristate.-   26. Transdermal therapeutic system according to any one of items 1    to 25, wherein the asenapine-containing matrix layer does not    comprise ethyl cellulose in an amount of 10-20% of the matrix layer    composition and preferably does not comprise ethyl cellulose.-   27. Transdermal therapeutic system according to any one of items 1    to 26, wherein the asenapine-containing matrix layer does not    comprise hydrogen chloride.-   28. Transdermal therapeutic system according to any one of items 1    to 27, wherein the asenapine-containing matrix layer does not    comprise toluene.-   29. Transdermal therapeutic system according to any one of items 1    to 28, wherein the asenapine-containing matrix layer is obtainable    by drying a coated coating composition wherein no hydrochloric acid    has been included in the coating composition.-   30. Transdermal therapeutic system according to any one of items 1    to 29, wherein the asenapine-containing matrix layer is obtainable    by drying a coated coating composition comprising no toluene.-   31. Transdermal therapeutic system according to any one of items 1    to 30, wherein the asenapine in the matrix layer composition is    included in the form of the free base.-   32. Transdermal therapeutic system according to any one of items 1    to 31, wherein the matrix layer composition is obtainable by    incorporating the asenapine in the form of the free base.-   33. Transdermal therapeutic system according to any one of items 1    to 32, wherein at least 90 mol %, preferably at least 95 mol %, more    preferably at least 98 mol % and most preferably at least 99 mol %    of the asenapine in the matrix layer is present in the form of the    free base.-   34. Transdermal therapeutic system according to any one of items 1    to 33, wherein the asenapine in the matrix layer is completely    dissolved.-   35. Transdermal therapeutic system according to any one of items 1    to 34, wherein the matrix layer composition contains asenapine    particles, preferably constituted of asenapine free base.-   36. Transdermal therapeutic system according to any one of items 1    to 35, wherein the amount of asenapine in the matrix layer    composition ranges from 2 to 20%, preferably from 3 to 15% and more    preferably from 4 to 12% of the matrix layer composition.-   37. Transdermal therapeutic system according to any one of items 1    to 36, wherein the asenapine has a purity of at least 95%,    preferably of at least 98% and more preferably of at least 99% as    determined by quantitative HPLC.-   38. Transdermal therapeutic system according to any one of items 1    to 37, wherein the matrix layer composition is a pressure-sensitive    adhesive composition.-   39. Transdermal therapeutic system according to any one of items 1    to 38, wherein the polymer is selected from pressure-sensitive    adhesive polymers.-   40. Transdermal therapeutic system according to any one of items 1    to 39, wherein the polymer is selected from acrylic polymers    comprising functional groups.-   41. Transdermal therapeutic system according to item 40, wherein the    functional groups are selected from hydroxyl groups, carboxylic acid    groups, neutralized carboxylic acid groups and mixtures thereof.-   42. Transdermal therapeutic system according to item 41, wherein the    functional groups are limited to hydroxyl groups.-   43. Transdermal therapeutic system according to any one of items 1    to 42, wherein the polymer is selected from acrylic polymers which    do not comprise carboxylic acid groups or neutralized carboxylic    acid groups or both groups.-   44. Transdermal therapeutic system according to any one of items 1    to 43, wherein the polymer is selected from acrylic polymers which    do not comprise acidic groups.-   45. Transdermal therapeutic system according to any one of items 1    to 44, wherein the polymer is selected from acrylic polymers    comprising hydroxyl groups and no carboxylic acid groups.-   46. Transdermal therapeutic system according to item 45, wherein the    polymer is a copolymer based on vinyl acetate,    2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and    glycidyl-methacrylate or a copolymer based on vinyl acetate,    2-ethylhexyl-acrylate and 2-hydroxyethyl-acrylate.-   47. Transdermal therapeutic system according to any one of items 39    to 46, wherein the polymer is cross-linked by a cross-linking agent    and preferably is cross-linked by an aluminium or a titanium    cross-linking agent.-   48. Transdermal therapeutic system according to any one of items 39    to 46, wherein the polymer is not cross-linked by a cross-linking    agent.-   49. Transdermal therapeutic system according to any one of items 1    to 48, wherein the polymer is selected from acrylic polymers    comprising no hydroxyl groups and no carboxylic acid groups.-   50. Transdermal therapeutic system according to item 49, wherein the    polymer is selected from acrylic polymers comprising no functional    groups.-   51. Transdermal therapeutic system according to item 50, wherein the    polymer is a copolymer based on methyl acrylate, 2-ethylhexyl    acrylate and t-octyl acrylamide, or a copolymer based on    2-ethylhexyl-acrylate and vinyl acetate.-   52. Transdermal therapeutic system according to any one of items 1    to 51, wherein the amount of the polymer ranges from 50 to 90%,    preferably from 60 to 85% and more preferably from 65 to 80% of the    matrix layer composition.-   53. Transdermal therapeutic system according to any one of items 1    to 52, wherein the total polymer content in the matrix layer    composition ranges from 60 to 95%, preferably from 70 to 90% and    more preferably from 75 to 85% of the matrix layer composition.-   54. Transdermal therapeutic system according to any one of items 1    to 53, wherein the transdermal therapeutic system has an area of    release of from 5 to 100 cm², preferably from 5 to 80 cm², and more    preferably from 10 to 50 cm² or from 50 to 80 cm², from 10 to 40 cm²    or from 10 to 30 cm² or from 55 to 65 cm².-   55. Transdermal therapeutic system according to any one of items 1    to 54, wherein the amount of asenapine contained in the transdermal    therapeutic system ranges from 5 to 100 mg, preferably from 10 to 80    mg, and most preferably from 15 to 60 mg.-   56. Transdermal therapeutic system according to any one of items 1    to 55, wherein the transdermal therapeutic system has an area of    release of from 5 to 100 cm², and the amount of asenapine contained    in the transdermal therapeutic system ranges from 5 to 100 mg.-   57. Transdermal therapeutic system according to any one of items 1    to 56, wherein the matrix layer composition comprises further    excipients or additives selected from the group consisting of    additional polymers, cross-linking agents, solubilizers, fillers,    tackifiers, plasticizers, stabilizers, softeners, substances for    skincare, permeation enhancers, pH regulators, and preservatives.-   58. Transdermal therapeutic system according to item 57, wherein the    tackifier is selected from polyethylene glycols, triglycerides,    dipropylene glycol, resins, resin esters, terpenes and derivatives    thereof, ethylene vinyl acetate adhesives, dimethylpolysiloxanes and    polybutenes, and mixtures thereof.-   59. Transdermal therapeutic system according to item 58, wherein the    matrix layer composition comprises medium chain triglycerides as    tackifier.-   60. Transdermal therapeutic system according to item 59, wherein the    matrix layer composition comprises medium chain triglycerides as    tackifier in an amount of from 0.1 to 14% of the matrix layer    composition, preferably from 1 to 13% of the matrix layer    composition, more preferably from 3 to 12% of the matrix layer    composition, and most preferably from 5 to 12% of the matrix layer    composition.-   61. Transdermal therapeutic system according to item 60, wherein the    matrix layer composition comprises medium chain triglycerides as    tackifier in an amount of about 10% of the matrix layer composition.-   62. Transdermal therapeutic system according to any one of items 59    to 61, wherein the fatty acid composition of the medium chain    triglycerides consists of one or more of    -   (i) Hexanoic acid,    -   (ii) Octanoic acid,    -   (iii) Decanoic acid,    -   (iv) Dodecanoic acid, and    -   (v) Tetradecanoic acid.-   63. Transdermal therapeutic system according to any one of items 59    to 62, wherein the fatty acid composition of the medium chain    triglycerides consists of    -   (i) 0 to 5% hexanoic acid,    -   (ii) 40.0 to 90.0% octanoic acid,    -   (iii) 10.0 to 55.0% decanoic acid,    -   (iv) 0 to 5% dodecanoic acid, and    -   (v) 0 to 2% tetradecanoic acid.-   64. Transdermal therapeutic system according to any one of items 59    to 63, wherein the fatty acid composition of the medium chain    triglycerides consists of    -   (i) 0 to 2% hexanoic acid,    -   (ii) 50.0 to 80.0% octanoic acid,    -   (iii) 20.0 to 45.0% decanoic acid,    -   (iv) 0 to 2% dodecanoic acid, and    -   (v) 0 to 1% tetradecanoic acid.-   65. Transdermal therapeutic system according to any one of items 59    to 64, wherein the fatty acid composition of the medium chain    triglycerides consists of    -   (i) 0 to 2% hexanoic acid,    -   (ii) 50.0 to 65.0% octanoic acid,    -   (iii) 30.0 to 45.0% decanoic acid,    -   (iv) 0 to 2% dodecanoic acid, and    -   (v) 0 to 1% tetradecanoic acid.-   66. Transdermal therapeutic system according to any one of items 59    to 64, wherein the fatty acid composition of the medium chain    triglycerides consists of    -   (i) 0 to 2% hexanoic acid,    -   (ii) 65.0 to 80.0% octanoic acid,    -   (iii) 20.0 to 35.0% decanoic acid,    -   (iv) 0 to 2% dodecanoic acid, and    -   (v) 0 to 1% tetradecanoic acid.-   67. Transdermal therapeutic system according to any one of items 59    to 66, wherein the acid value of the medium chain triglycerides is    0.5 mg KOH/g or less, preferably 0.2 mg KOH/g or less and most    preferably 0.1 mg KOH/g or less.-   68. Transdermal therapeutic system according to any one of items 59    to 67, wherein the peroxide value of the medium chain triglycerides    is 5.0 mequi O/kg or less, preferably 2.0 mequi O/kg or less and    most preferably 1.0 mequi O/kg or less.-   69. Transdermal therapeutic system according to any one of items 59    to 68, wherein the hydroxyl value of the medium chain triglycerides    is 10 mg KOH/g or less, preferably 8.0 mg KOH/g or less and most    preferably 5.0 mg KOH/g or less.-   70. Transdermal therapeutic system according to item 57, wherein the    stabilizer is selected from sodium metabisulfite, ascorbic acid and    ester derivatives thereof, butylated hydroxytoluene, tocopherol and    ester derivatives thereof such as tocopheryl acetate and tocopheryl    linoleate, as well as any combination thereof.-   71. Transdermal therapeutic system according to item 57, wherein the    permeation enhancer is selected from diethylene glycol monoethyl    ether, diisopropyl adipate, isopropyl myristate, isopropyl    palmitate, lauryl lactate, dimethylpropylene urea and a mixture of    propylene glycol monoesters and diesters of fatty acids.-   72. Transdermal therapeutic system according to any one of items 1    to 71, wherein the matrix layer composition does not comprise a    permeation enhancer selected from oleic acids, triglycerides, oleic    alcohols, and mixtures thereof.-   73. Transdermal therapeutic system according to any one of items 1    to 72, wherein the matrix layer composition does not comprise a    permeation enhancer.-   74. Transdermal therapeutic system according to any one of items 1    to 73, providing a cumulative skin permeation rate of asenapine at    hour 48 or at hour 72 as measured in a Franz diffusion cell with    dermatomed human skin of 1 μg/(cm² h) to 20 μg/(cm² h), preferably    of 2 μg/(cm² h) to 15 μg/(cm² h) and more preferably of 4 μg/(cm² h)    to 12 μg/(cm² h).-   75. Transdermal therapeutic system according to any one of items 1    to 74, providing a skin permeation rate of asenapine as measured in    a Franz diffusion cell with dermatomed human skin of    -   0 μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours,    -   2 μg/(cm² h) to 20 μg/(cm² h) from hour 8 to hour 24,    -   3 μg/(cm² h) to 20 μg/(cm² h) from hour 24 to hour 32,    -   3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour 48,    -   2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour 72.-   76. Transdermal therapeutic system according to any one of items 1    to 75, providing a cumulative permeated amount of asenapine as    measured in a Franz diffusion cell with dermatomed human skin of    0.05 mg/cm² to 1.0 mg/cm², preferably of 0.1 mg/cm² to 0.7 mg/cm²    over a time period of 48 hours.-   77. Transdermal therapeutic system according to any one of items 1    to 76, providing a cumulative permeated amount of asenapine as    measured in a Franz diffusion cell with dermatomed human skin of 0.1    mg/cm² to 2.0 mg/cm², preferably 0.2 mg/cm² to 1.0 mg/cm² over a    time period of 72 hours.-   78. Transdermal therapeutic system according to any one of items 1    to 77, wherein the matrix layer contains initially an amount of    asenapine of at least 95%, preferably of at least 96%, more    preferably of at least 97% and even more preferably of at least 98%    of the theoretical amount of asenapine included in the matrix layer.-   79. Transdermal therapeutic system according to any one of items 1    to 78, wherein the matrix layer contains, after having been stored    at 25° C. and 60% relative humidity for at least 2 months,    preferably at least 3 months, an amount of asenapine of at least    90%, preferably of at least 92%, more preferably of at least 94% and    even more preferably of at least 95% of the theoretical amount of    asenapine included in the matrix layer.-   80. Transdermal therapeutic system according to any one of items 1    to 79, wherein the matrix layer contains, after having been stored    at 40° C. and 75% relative humidity for at least 2 months,    preferably at least 3 months, an amount of asenapine of at least    88%, preferably of at least 90%, more preferably of at least 91% and    even more preferably of at least 92% of the theoretical amount of    asenapine included in the matrix layer.-   81. Transdermal therapeutic system according to any one of items 1    to 80, wherein the matrix layer contains initially a total amount of    asenapine-related degradation substances of less than 0.7%,    preferably of less than 0.5%, more preferably of less than 0.3% and    even more preferably of less than 0.2%.-   82. Transdermal therapeutic system according to any one of items 1    to 81, wherein the matrix layer contains, after having been stored    at 25° C. and 60% relative humidity for at least 2 months,    preferably at least 3 months, a total amount of asenapine-related    degradation substances of less than 1.0%, preferably of less than    0.7%, more preferably of less than 0.5% and even more preferably of    less than 0.4%.-   83. Transdermal therapeutic system according to any one of items 1    to 79, wherein the matrix layer contains, after having been stored    at 40° C. and 75% relative humidity for at least 2 months,    preferably at least 3 months, a total amount of asenapine-related    degradation substances of less than 3.0%, preferably of less than    2.0%, more preferably of less than 1.5% and even more preferably of    less than 0.7%.-   84. Transdermal therapeutic system according to any one of items 1    to 83, further comprising a release liner.-   85. Transdermal therapeutic system according to any one of items 1    to 84, further comprising an adhesive overlay or comprising no    adhesive overlay, and preferably comprising no adhesive overlay.-   86. Transdermal therapeutic system according to any one of items 1    to 85, wherein the backing layer is substantially    asenapine-impermeable.-   87. Transdermal therapeutic system according to any one of items 1    to 86, wherein the self-adhesive layer structure does not comprise    an additional skin contact layer.-   88. Transdermal therapeutic system according to any one of items 1    to 87, wherein the self-adhesive layer structure comprises an    additional skin contact layer.-   89. Transdermal therapeutic system according to item 88, wherein the    self-adhesive layer structure comprises a membrane which is located    between the matrix layer and the additional skin contact layer,    wherein the membrane is preferably a rate controlling membrane.-   90. Transdermal therapeutic system according to any one of items 1    to 89, wherein the self-adhesive layer structure comprises an    additional reservoir layer which is located between the backing    layer and the matrix layer, and a further rate controlling membrane    which is located between the additional reservoir layer and the    matrix layer.-   91. Transdermal therapeutic system according to any one of items 1    to 90, wherein the transdermal therapeutic system is a matrix-type    TTS.-   92. Transdermal therapeutic system according to any one of items 1    to 91 for use in a method of treatment, preferably for use in a    method of treating psychosis and more preferably for use in a method    of treating one or more conditions selected from schizophrenia,    bipolar disorder, posttraumatic stress disorder, major depressive    disorder, dementia related psychosis, agitation and manic disorder.-   93. Transdermal therapeutic system according to item 92 for use in a    method of treating schizophrenia and/or bipolar disorder.-   94. Transdermal therapeutic system according to item 92 for use in a    method of treating bipolar disorder, in particular acute manic or    mixed episodes of bipolar disorder.-   95. Transdermal therapeutic system according to any one of items 92    to 94 for use in a method of treatment with a dosing interval of at    least 24 hours or 1 day, at least 48 hours or 2 days, or at least 72    hours or 3 days.-   96. Transdermal therapeutic system according to any one of items 92    to 95 for use in a method of treatment with a dosing interval of up    to 168 hours or 7 days, up to 120 hours or 5 days, or up to 96 hours    or 4 days.-   97. Transdermal therapeutic system according to item 95 for use in a    method of treatment with a dosing interval of 24 hours or 1 day.-   98. Transdermal therapeutic system according to item 95 for use in a    method of treatment with a dosing interval of 48 hours or 2 days.-   99. Transdermal therapeutic system according to item 95 for use in a    method of treatment with a dosing interval of 84 hours or 3.5 days.-   100. Transdermal therapeutic system according to any one of items 92    to 99 for use in a method of treating a patient,    -   wherein the transdermal therapeutic system provides a reduction        in at least one asenapine-related side effect relative to an        equivalent dose of sublingual asenapine.-   101. Transdermal therapeutic system according to item 94 for use in    a method of treating a patient, wherein    -   the patient is a human patient suffering from fatigue,        somnolence, dizziness, or any combination thereof, or    -   the at least one asenapine-related side effect is fatigue,        somnolence, dizziness, oral hypoaesthesia, or any combination        thereof, or    -   the incidence of the at least one asenapine-related side effect        relative to an equivalent dose of sublingual asenapine is        reduced by at least about 30%, at least about 40%, at least        about 70% or at least about 80%, and/or the intensity of the at        least one asenapine-related side effect relative to an        equivalent dose of sublingual asenapine is reduced, or    -   the at least one asenapine-related side effect is fatigue and        the incidence of fatigue relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30% or at        least about 40% and/or the intensity of fatigue relative to an        equivalent dose of sublingual asenapine is reduced, or    -   the at least one asenapine-related side effect is dizziness, and        the incidence of dizziness relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30%, at least        about 40%, at least about 70% or at least about 80%.-   102. Transdermal therapeutic system according to any one of items 1    to 101 for use in a method of reducing, in a patient, at least one    asenapine-related side effect relative to an equivalent dose of    sublingual asenapine.-   103. Transdermal therapeutic system according to item 102 for use in    a method of reducing, in a patient, at least one asenapine-related    side effect relative to an equivalent dose of sublingual asenapine,    wherein    -   the patient is a human patient suffering from fatigue,        somnolence, dizziness, or any combination thereof, or    -   the at least one asenapine-related side effect is fatigue,        somnolence, dizziness, oral hypoaesthesia, or any combination        thereof, or    -   the incidence of the at least one asenapine-related side effect        relative to an equivalent dose of sublingual asenapine is        reduced by at least about 30%, at least about 40%, at least        about 70% or at least about 80%, and/or the intensity of the at        least one asenapine-related side effect relative to an        equivalent dose of sublingual asenapine is reduced, or    -   the at least one asenapine-related side effect is fatigue and        the incidence of fatigue relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30% or at        least about 40% and/or the intensity of fatigue relative to an        equivalent dose of sublingual asenapine is reduced, or    -   the at least one asenapine-related side effect is dizziness and        the incidence of dizziness relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30%, at least        about 40%, at least about 70% or at least about 80%.-   104. A method of treatment, and in particular a method of treating    psychosis and more preferably a method of treating one or more    conditions selected from schizophrenia, bipolar disorder,    posttraumatic stress disorder, major depressive disorder, dementia    related psychosis, agitation and manic disorder-   including applying a transdermal therapeutic system according to any    one of items 1 to 91 to the skin of a patient.-   105. A method of treating schizophrenia and/or bipolar disorder    including applying a transdermal therapeutic system according to any    one of items 1 to 91 to the skin of a patient.-   106. A method of treating bipolar disorder and in particular acute    manic or mixed episodes of bipolar disorder-   including applying a transdermal therapeutic system according to any    one of items 1 to 91 to the skin of a patient.-   107. A method of treatment according to any one of items 104 to 106    including applying a transdermal therapeutic system according to any    one of items 1 to 91 for at least 24 hours or 1 day, at least 48    hours or 2 days, or at least 72 hours or 3 days to the skin of a    patient.-   108. A method of treatment according to any one of items 104 to 106    including applying a transdermal therapeutic system according to any    one of items 1 to 91 for up to 168 hours or 7 days, up to 120 hours    or 5 days, or up to 96 hours or 4 days to the skin of a patient.-   109. A method of treatment according to any one of items 104 to 106    including applying a transdermal therapeutic system according to any    one of items 1 to 91 for 24 hours or 1 day to the skin of a patient.-   110. A method of treatment according to any one of items 104 to 106    including applying a transdermal therapeutic system according to any    one of items 1 to 91 for 48 hours or 2 days to the skin of a    patient.-   111. A method of treatment according to any one of items 104 to 106    including applying a transdermal therapeutic system according to any    one of items 1 to 91 for 84 hours or 3.5 days to the skin of a    patient.-   112. The method of treatment according to any one of items 104 to    111, wherein the transdermal therapeutic system provides a reduction    in at least one asenapine-related side effect relative to an    equivalent dose of sublingual asenapine.-   113. The method of treatment according to item 112, wherein the    patient is a human patient suffering from fatigue, somnolence,    dizziness, or any combination thereof.-   114. The method of treatment according to item 112 or 113, wherein    the at least one asenapine-related side effect is fatigue,    somnolence, dizziness, oral hypoaesthesia, or any combination    thereof.-   115. The method of treatment according to any one of items 112 to    114, wherein the incidence of the at least one asenapine-related    side effect relative to an equivalent dose of sublingual asenapine    is reduced by at least about 30%, at least about 40%, at least about    70% or at least about 80%, and/or wherein the intensity of the at    least one asenapine-related side effect relative to an equivalent    dose of sublingual asenapine is reduced.-   116. The method of treatment according to item 115, wherein    -   the at least one asenapine-related side effect is fatigue and        the incidence of fatigue relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30% or at        least about 40% and/or the intensity of fatigue relative to an        equivalent dose of sublingual asenapine is reduced, or    -   the at least one asenapine-related side effect is dizziness and        the incidence of dizziness relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30%, at least        about 40%, at least about 70% or at least about 80%.-   117. A method of reducing, in a patient, at least one    asenapine-related side effect relative to an equivalent dose of    sublingual asenapine, the method comprising administering a    transdermal therapeutic system according to any one of items 1 to    91.-   118. The method according to item 117, wherein the patient is a    human patient suffering from fatigue, somnolence, dizziness, or any    combination thereof.-   119. The method according to item 117 or 118, wherein the at least    one asenapine-related side effect is fatigue, somnolence, dizziness,    oral hypoaesthesia, or any combination thereof.-   120. The method according to any one of items 117 to 119 wherein the    incidence of the at least one asenapine-related side effect relative    to an equivalent dose of sublingual asenapine is reduced by at least    about 30%, at least about 40%, at least about 70% or at least about    80%, and/or wherein the intensity of the at least one    asenapine-related side effect relative to an equivalent dose of    sublingual asenapine is reduced.-   121. The method according to item 120, wherein    -   the at least one asenapine-related side effect is fatigue and        the incidence of fatigue relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30% or at        least about 40% and/or the intensity of fatigue relative to an        equivalent dose of sublingual asenapine is reduced, or    -   the at least one asenapine-related side effect is dizziness and        the incidence of dizziness relative to an equivalent dose of        sublingual asenapine is reduced by at least about 30%, at least        about 40%, at least about 70% or at least about 80%.-   122. A method of reducing at least one asenapine-related side effect    in a patient being treated with sublingual asenapine therapy, the    method comprising:    -   a) discontinuing sublingual asenapine therapy; and    -   b) administering a transdermal therapeutic system according to        any of items 1 to 91 to the skin of the patient, wherein the        transdermal therapeutic system provides a reduction in at least        one asenapine-related side effect relative to an equivalent dose        of sublingual asenapine.-   123. The method of item 122, wherein the transdermal therapeutic    system delivers an amount of asenapine equivalent to the amount of    asenapine originally provided by the sublingual asenapine therapy.-   124. Process of manufacture of a matrix layer for use in a    transdermal therapeutic system according to any one of items 1 to    103 comprising the steps of:    -   1) combining at least the components asenapine, acrylic polymer,        additional polymer, α-tocopherol and ascorbyl palmitate, in a        solvent to obtain a coating composition;    -   2) coating the coating composition onto a backing layer or a        release liner or any intermediate liner; and    -   3) drying the coated coating composition to form the matrix        layer.-   125. The process according to item 124, wherein in step 1) at least    the components asenapine, acrylic polymer, additional polymer,    α-tocopherol, ascorbyl palmitate and sodium metabisulfite are    combined in a solvent to obtain the coating composition.-   126. The process according to item 124 or 125, wherein in step 1)    the asenapine is dissolved to obtain a coating composition.-   127. The process according to any one of items 124 to 126, wherein    preferably the solvent is selected from alcoholic solvents, in    particular methanol, ethanol, isopropanol and mixtures thereof, and    from non-alcoholic solvents, in particular ethyl acetate, hexane,    n-heptane, heptanes, petroleum ether, toluene, and mixtures thereof,    and more preferably is selected from ethanol and ethyl acetate.-   128. The process according to any one of items 124 to 127, wherein    the polymer is an acrylic polymer and preferably a copolymer based    on vinyl acetate, 2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and    glycidyl-methacrylate or a copolymer based on vinyl acetate,    2-ethylhexyl-acrylate and 2-hydroxyethyl-acrylate, which is provided    as a solution and preferably as a solution in ethyl acetate,    n-heptane, heptanes, methanol, ethanol, or any mixtures thereof,    with a solids content of from 30 to 60% by weight.-   129. The process according to any one of items 124 to 128, wherein    the polymer is an acrylic polymer and wherein the polymer is    cross-linked.-   130. The process according to item 123, wherein no additional    cross-linking agent is used in step 1) to obtain the coating    composition.-   131. The process according to any one of items 124 to 128, wherein    the polymer is an acrylic polymer and wherein the polymer is not    cross-linked.-   132. The process according to item 131, wherein an additional    cross-linking agent is used in step 1) to obtain the coating    composition, wherein the cross-linking agent preferably is an    aluminium or a titanium cross-linking agent.-   133. The process according to any one of items 124 to 132, wherein    drying is performed in one or more cycles at room temperature and/or    at a temperature of from 65 to 100° C., more preferably from 70 to    90° C.-   134. Transdermal therapeutic system for the transdermal    administration of asenapine comprising a self-adhesive layer    structure comprising:    -   A) a backing layer;    -   B) an asenapine-containing matrix layer consisting of a matrix        layer composition comprising:        -   1 asenapine included in the form of the free base;        -   2. a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and            glycidyl-methacrylate or a copolymer based on vinyl acetate,            2-ethylhexyl-acrylate and 2-hydroxyethyl-acrylate;        -   3. medium chain triglycerides in an amount of from 5 to 12%            of the matrix layer composition;        -   4. soluble polyvinylpyrrolidone in an amount of from 5 to            15% of the matrix layer composition; and        -   5. α-tocopherol in an amount of from 0.025 to 0.1% of the            matrix layer composition, ascorbyl palmitate in an amount of            from 0.15 to 0.5% of the matrix layer composition, and            sodium metabisulfite in an amount of from 0.05 to 0.15% of            the matrix layer composition, as stabilizers;

1. Transdermal therapeutic system for the transdermal administration ofasenapine comprising a self-adhesive layer structure containing atherapeutically effective amount of asenapine, said self-adhesive layerstructure comprising: A) a backing layer; B) an asenapine-containingmatrix layer consisting of a matrix layer composition comprising: 1.asenapine;
 2. a polymer selected from acrylic polymers;
 3. an additionalpolymer; and
 4. α-tocopherol in an amount of from 0.01 to 2% of thematrix layer composition and ascorbyl palmitate in an amount of at least0.01% of the matrix layer composition as stabilizers.
 2. Transdermaltherapeutic system according to claim 1, wherein the matrix layercomposition further comprises sodium metabisulfite in an amount of from0 to 0.5%, preferably from 0.01 to 0.2%, more preferably from 0.05 to0.15% and even more preferably in an amount of about 0.1% of the matrixlayer composition as stabilizer.
 3. Transdermal therapeutic systemaccording to any one of claims 1 to 2, wherein the matrix layercomposition comprises α-tocopherol in an amount of at least 0.025% ofthe matrix layer composition, and/or wherein the matrix layercomposition comprises α-tocopherol in an amount of up to 1.5% or 0.75%,preferably up to 0.5%, and more preferably up to 0.1% of the matrixlayer composition, wherein preferably the matrix layer compositioncomprises α-tocopherol in an amount of about 0.05% of the matrix layercomposition.
 4. Transdermal therapeutic system according to any one ofclaims 1 to 3, wherein the matrix layer composition comprises ascorbylpalmitate in an amount of at least 0.02%, preferably at least 0.08%, andmore preferably at least 0.15% of the matrix layer composition, and/orwherein the matrix layer composition comprises ascorbyl palmitate in anamount of up to 2.0 or 1.0%, and preferably up to 0.6% of the matrixlayer composition, wherein more preferably the matrix layer compositioncomprises ascorbyl palmitate in an amount of from 0.2 to 0.4% of thematrix layer composition.
 5. Transdermal therapeutic system according toany one of claims 1 to 4, wherein the additional polymer is selectedfrom polymers which provide for an improved water and/or moistureabsorption of the matrix layer, and more preferably frompolyvinylpyrrolidones, and most preferably from solublepolyvinylpyrrolidones, and/or wherein the additional polymer is apolyvinylpyrrolidone having a K-Value within a range selected from thegroup of ranges consisting of 9 to 15, and preferably 10.2 to 13.8, 15to 20, and preferably 15.3 to 18.4, 20 to 27, and preferably 22.5 to27.0, 27 to 35, and preferably 27.0 to 32.4, and 75 to 110, andpreferably 81.0 to 97.2, or any mixtures thereof, and preferably is apolyvinylpyrrolidone having a K-Value within a range of 27.0 to 32.4 orof 81.0 to 97.2, and more preferably is a polyvinylpyrrolidone having aK-Value within range of 27.0 to 32.4.
 6. Transdermal therapeutic systemaccording to claim 5, wherein the matrix layer composition comprises anadditional polymer selected from polyvinylpyrrolidones, and preferablyfrom soluble polyvinylpyrrolidones, in an amount of from 0 to 20% of thematrix layer composition, preferably from 5 to 15% of the matrix layercomposition and more preferably in an amount of about 10% of the matrixlayer composition.
 7. Transdermal therapeutic system according to anyone of claims 1 to 6, wherein the transdermal therapeutic systemcontains at least 0.70 mg/cm², preferably at least 0.80 mg/cm², morepreferably at least 0.82 mg/cm² and most preferably at least 0.83 mg/cm²asenapine.
 8. Transdermal therapeutic system according to any one ofclaims 1 to 7, wherein the asenapine in the matrix layer composition isincluded in the form of the free base.
 9. Transdermal therapeutic systemaccording to any one of claims 1 to 8, wherein at least 90 mol %,preferably at least 95 mol %, more preferably at least 98 mol % and mostpreferably at least 99 mol % of the asenapine in the matrix layer ispresent in the form of the free base.
 10. Transdermal therapeutic systemaccording to any one of claims 1 to 9, wherein the amount of asenapinein the matrix layer composition ranges from 2 to 20%, preferably from 3to 15% and more preferably from 4 to 12% of the matrix layercomposition.
 11. Transdermal therapeutic system according to any one ofclaims 1 to 10, wherein the polymer is selected from pressure-sensitiveadhesive polymers. wherein preferably the polymer is selected fromacrylic polymers comprising hydroxyl groups and no carboxylic acidgroups and more preferably is a copolymer based on vinyl acetate,2-ethylhexyl-acrylate, 2-hydroxyethyl-acrylate and glycidyl-methacrylateor a copolymer based on vinyl acetate, 2-ethylhexyl-acrylate and2-hydroxyethyl-acrylate.
 12. Transdermal therapeutic system according toclaim 11, wherein the polymer is cross-linked by a cross-linking agentand preferably is cross-linked by an aluminium or a titaniumcross-linking agent.
 13. Transdermal therapeutic system according to anyone of claims 1 to 12, wherein the amount of the polymer ranges from 50to 90%, preferably from 60 to 85% and more preferably from 65 to 80% ofthe matrix layer composition.
 14. Transdermal therapeutic systemaccording to any one of claims 1 to 13, wherein the matrix layercomposition comprises a tackifier selected from polyethylene glycols,triglycerides, dipropylene glycol, resins, resin esters, terpenes andderivatives thereof, ethylene vinyl acetate adhesives,dimethylpolysiloxanes and polybutenes, and mixtures thereof, whereinpreferably the matrix layer composition comprises medium chaintriglycerides as tackifier.
 15. Transdermal therapeutic system accordingto claim 14, wherein the matrix layer composition comprises medium chaintriglycerides as tackifier in an amount of from 0.1 to 14% of the matrixlayer composition, preferably from 1 to 13% of the matrix layercomposition, more preferably from 3 to 12% of the matrix layercomposition, even more preferably from 5 to 12% of the matrix layercomposition, and most preferably in an amount of about 10% of the matrixlayer composition.
 16. Transdermal therapeutic system according to anyone of claims 1 to 15, providing a cumulative skin permeation rate ofasenapine at hour 48 or at hour 72 as measured in a Franz diffusion cellwith dermatomed human skin of 1 μg/(cm² h) to 20 μg/(cm² h), preferablyof 2 μg/(cm² h) to 15 μg/(cm² h) and more preferably of 4 μg/(cm² h) to12 μg/(cm² h), and/or providing a skin permeation rate of asenapine asmeasured in a Franz diffusion cell with dermatomed human skin of 0μg/(cm² h) to 10 μg/(cm² h) in the first 8 hours, 2 μg/(cm² h) to 20μg/(cm² h) from hour 8 to hour 24, 3 μg/(cm² h) to 20 μg/(cm² h) fromhour 24 to hour 32, 3 μg/(cm² h) to 20 μg/(cm² h) from hour 32 to hour48, 2 μg/(cm² h) to 15 μg/(cm² h) from hour 48 to hour
 72. 17.Transdermal therapeutic system according to any one of claims 1 to 16,wherein the matrix layer contains initially an amount of asenapine of atleast 95%, preferably of at least 96%, more preferably of at least 97%and even more preferably of at least 98% of the theoretical amount ofasenapine included in the matrix layer, and/or wherein the matrix layercontains, after having been stored at 25° C. and 60% relative humidityfor at least 2 months, preferably at least 3 months, an amount ofasenapine of at least 90%, preferably of at least 92%, more preferablyof at least 94% and even more preferably of at least 95% of thetheoretical amount of asenapine included in the matrix layer, and/orwherein the matrix layer contains, after having been stored at 40° C.and 75% relative humidity for at least 2 months, preferably at least 3months, an amount of asenapine of at least 88%, preferably of at least90%, more preferably of at least 91% and even more preferably of atleast 92% of the theoretical amount of asenapine included in the matrixlayer.
 18. Transdermal therapeutic system according to any one of claims1 to 17, wherein the matrix layer contains initially a total amount ofasenapine-related degradation substances of less than 0.7%, preferablyof less than 0.5%, more preferably of less than 0.3% and even morepreferably of less than 0.2%, and/or wherein the matrix layer contains,after having been stored at 25° C. and 60% relative humidity for atleast 2 months, preferably at least 3 months, a total amount ofasenapine-related degradation substances of less than 1.0%, preferablyof less than 0.7%, more preferably of less than 0.5% and even morepreferably of less than 0.4%, and/or wherein the matrix layer contains,after having been stored at 40° C. and 75% relative humidity for atleast 2 months, preferably at least 3 months, a total amount ofasenapine-related degradation substances of less than 3.0%, preferablyof less than 2.0%, more preferably of less than 1.5% and even morepreferably of less than 0.7%.
 19. Transdermal therapeutic systemaccording to any one of claims 1 to 18 for use in a method of treatment,preferably for use in a method of treating psychosis and more preferablyfor use in a method of treating one or more conditions selected fromschizophrenia, bipolar disorder, posttraumatic stress disorder, majordepressive disorder, dementia related psychosis, agitation and manicdisorder, in particular acute manic or mixed episodes of bipolardisorder.
 20. A method of treatment, and in particular a method oftreating psychosis and more preferably a method of treating one or moreconditions selected from schizophrenia, bipolar disorder, posttraumaticstress disorder, major depressive disorder, dementia related psychosis,agitation and manic disorder, in particular acute manic or mixedepisodes of bipolar disorder, including applying a transdermaltherapeutic system according to any one of claims 1 to 18 to the skin ofa patient.
 21. Process of manufacture of a matrix layer for use in atransdermal therapeutic system according to any one of claims 1 to 19comprising the steps of: 1) combining at least the components asenapine,acrylic polymer, additional polymer, α-tocopherol and ascorbylpalmitate, in a solvent to obtain a coating composition; 2) coating thecoating composition onto a backing layer or a release liner or anyintermediate liner; and 3) drying the coated coating composition to formthe matrix layer.